The SAGES Manual of Fluorescence-Guided Surgery 3031406842, 9783031406843

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The SAGES Manual of FluorescenceGuided Surgery Nova Szoka · David Renton · Santiago Horgan   Editors

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The SAGES Manual of Fluorescence-Guided Surgery

Nova Szoka  •  David Renton Santiago Horgan Editors

The SAGES Manual of Fluorescence-Guided Surgery

Editors Nova Szoka Department of Surgery West Virginia University Morgantown, WV, USA

David Renton Division of General Surgery Ohio State University Columbus, OH, USA

Santiago Horgan Department of Surgery University of California, San Diego San Diego, CA, USA

ISBN 978-3-031-40684-3    ISBN 978-3-031-40685-0 (eBook) https://doi.org/10.1007/978-3-031-40685-0 © Society of American Gastrointestinal and Endoscopic Surgeons 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

For my family who is my foundation and my heart. -Nova Szoka

Introduction

Fluorescence-Guided Surgery (FGS), an innovative technology based on real-time intraoperative image guidance, has been transforming surgical practice in recent years. Currently, the most popular method of FGS uses a near infrared (NIR) fluorescent dye or a NIR emitting light source to identify anatomic structures, target surgical pathology during surgical procedures, or assess perfusion to an area of interest, thus providing surgeons with objective information that can enhance both surgical performance and surgical outcomes. In this book, we will explore the world of FGS, delving into its history, current applications, and future potential. We will examine the science behind this technique and explore the use of NIR infrared imaging in multiple surgical specialties, as well as examine novel fluorescence agents and modalities. Expert surgeons from a comprehensive list of surgical subspecialties were enlisted to share their experience using FGS, and this manual can be used as a guide for surgeons who are interested in incorporating FGS into their practice. The first two chapters in this manual introduce the history and science of immunofluorescence and provide a comprehensive review of current fluorescence-guided platforms and devices; the remaining chapters discuss florescence-guided imaging within a specific surgical subspecialty and include background information, indications for use, a technical description of the procedure(s), and a review of potential pitfalls. Each of these chapters also

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describes the level of evidence for FGS supported by current ­publications. Chapter content is augmented by color images and videos. Whether you are a surgeon, a medical professional, or simply someone with an interest in the latest advances in medical technology, this book will provide you with a comprehensive overview of Fluorescence-Guided Surgery, its current applications, and its exciting potential for the future. The editors would like to thank the authors who contributed to this book, who are pioneers within a blossoming field of surgical imaging, as well as thank SAGES and Springer for supporting this work.

Contents

1 History  and Science of Immunofluorescence��������������  1 Ludovica Baldari, Luigi Boni, and Elisa Cassinotti 2 Current Fluorescence-­Guided Platforms and Devices���������������������������������������������������������������������������� 31 Donovan Hui, Kevin Carroll, Christina Sanders, and David Pechman 3 Use  of Fluorescence Guidance in Colorectal Surgery���������������������������������������������������������������������������� 87 Michael R. Freund, Anna Duprée, and Steven D. Wexner 4 Use  of Fluorescence Guidance in Cholecystectomy��������������������������������������������������������123 Ryan C. Broderick, David Renton, and Santiago Horgan 5 Use  of Fluorescence Guidance in Hepatic Surgery����������������������������������������������������������������������������135 Iswanto Sucandy, Emanuel Shapera, and Takeaki Ishizawa 6 Use  of Fluorescence Guidance in Endocrine Surgery����������������������������������������������������������������������������157 Jared Matson, Thinzar M. Lwin, and Michael Bouvet 7 Use  of Fluorescence Guidance in Bariatric Surgery����������������������������������������������������������������������������193 Edmund B. Chen, Mark A. Burroughs, Andrea Trinh, Sachin Kukreja, and Keri A. Seymour

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8 Use  of Fluorescence Guidance in Breast Reconstruction����������������������������������������������������������������231 Acara Turner, Luis Quiroga, Sebastian Brooke, and Kerri Woodberry 9 Use  of Fluorescence Guidance in Plastic and Reconstructive Surgery: Skin and Muscle Flaps��������257 Zachary A. Koenig, Cristiane M. Ueno, Jack J. Gelman, and Kerri Woodberry 10 Use  of Fluorescence Guidance in Burn Surgery ��������275 Apinut Wongkietkachorn, Palakorn Surakunprapha, Supawich Wongkietkachorn, Sarinya Boonpoapichart, and Phachara Longmeewong 11 Use  of Fluorescence Guidance in Acute Care Surgery and Trauma������������������������������������������������������307 Elwin Tham, Jennifer Knight, and Nova Szoka 12 Use  of Fluorescence Guidance in Pediatric Surgery����������������������������������������������������������������������������337 Stefan Scholz, Hannah Rinehardt, Ranjeet S. Kalsi, Jillian C. Jacobson, and Samir Pandya 13 Use  of Fluorescence Guidance in Neurosurgery ��������385 Brendan Jones and Maxwell Almenoff 14 Use  of Fluorescence Guidance in Cardiothoracic Surgery��������������������������������������������403 Derek Muehrcke 15 Use  of Fluorescence Guidance in Urologic Surgery����������������������������������������������������������������������������435 David Zekan, Andrew Williams, Amr Elbakry, and Adam Luchey 16 Use  of Fluorescence Guidance in Gynecology ������������463 Lioudmila Lipetskaia, Barbara Diane Gillis, and Courtney Griffiths 17 Future  Directions in Fluorescence-and Image-­Guided Surgery��������������������������������������������������487 Gene Yang Index����������������������������������������������������������������������������������������501

Contributors

Maxwell  Almenoff, MD Department of Cardiovascular and Thoracic Surgery, Vascular Surgery, West Virginia University Heart and Vascular Institute, Morgantown, WV, USA Ludovica Baldari, MD  Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Luigi Boni, MD  Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Department of Scienze Cliniche e delle Comunità, University of Milan, Milan, Italy Sarinya  Boonpoapichart, MD  Division of Plastic and Reconstructive Surgery, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Michael  Bouvet, MD  Department of Surgery, UC San Diego, San Diego, CA, USA VA San Diego Healthcare System, San Diego, CA, USA Ryan  C.  Broderick, MD  Division of Minimally Invasive Surgery, Department of Surgery, University of California San Diego, La Jolla, CA, USA Sebastian  Brooke, MD Department of Surgery, Division of Plastic, Reconstructive, and Hand Surgery, West Virginia University School of Medicine, Morgantown, WV, USA

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Mark A. Burroughs  Department of Surgery, Methodist Dallas Medical Center, Dallas, TX, USA Kevin  Carroll, MBBS Department of Surgery, Northwell Health—South Shore University Hospital, Bay Shore, NY, USA Elisa  Cassinotti, MD, PhD  Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Department of Scienze Cliniche e delle Comunità, University of Milan, Milan, Italy Edmund B. Chen, MD  Department of Surgery, School of Medicine, Duke University, Durham, NC, USA Anna  Duprée, MD  Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Amr  Elbakry, MD West Virginia University Department of Urology, Morgantown, WV, USA Michael R. Freund, MD  Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA Department of General Surgery, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel Jack J. Gelman, MD  Department of Surgery, Division of Plastic and Reconstructive Surgery, West Virginia University School of Medicine, Morgantown, WV, USA Barbara  Diane  Gillis, BS West Virginia University School of Medicine, Morgantown, WV, USA Courtney  Griffiths, DO Division of Gynecology Oncology, Cooper Medical School for Rowan University, Camden, NJ, USA Santiago  Horgan, MD Department of Surgery, University of California, San Diego, San Diego, CA, USA

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Donovan Hui, MD  Department of Surgery, New York Medical College Metropolitan Hospital Center, New York, NY, USA Takeaki  Ishizawa, MD, PhD, FACS Department of Hepatobiliary-­Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Abeno-ku, Osaka, Japan Jillian  C.  Jacobson, MD Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA Brendan Jones, MD  Department of General Surgery, West Virginia University School of Medicine, Morgantown, WV, USA Ranjeet  S.  Kalsi, MD  Division of Pediatric General and Thoracic Surgery, Department of Surgery, University of Pittsburgh Medical Center/Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Jennifer Knight, MD, FACS  Department of Surgery, The Ohio State University, Werner Medical Center, Columbus, OH, USA Zachary  A.  Koenig, MD Department of Surgery, Division of Plastic and Reconstructive Surgery, West Virginia University School of Medicine, Morgantown, WV, USA Sachin Kukreja  Department of Surgery, Methodist Dallas Medical Center, Dallas, TX, USA Dallas-Fort Worth Bariatrics and General Surgery, Dallas, TX, USA Lioudmila  Lipetskaia, MD, MSc  Division of Urogynecology, Department of Obstetrics and Gynecology, Cooper Medical School for Rowan University, Camden, NJ, USA Phachara Longmeewong, MD  Division of Plastic and Reconstructive Surgery, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Adam  Luchey, MD West Virginia University Department of Urology, Morgantown, WV, USA Thinzar M. Lwin, MD  Department of Surgery, UC San Diego, San Diego, CA, USA

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Department of Surgical Oncology, Dana Farber Cancer Center, Boston, MA, USA Jared Matson, MD  Department of Surgery, UC San Diego, San Diego, CA, USA Derek Muehrcke, MD, FACS  Cardiovascular and Thoracic Surgery at Flagler Hospital, Saint Augustine, FL, USA Samir Pandya, MD  Division of Pediatric Surgery, Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA David Pechman, MD  Department of Surgery, Zucker School of Medicine at Hofstra, Northwell Health—South Shore University Hospital, Bay Shore, NY, USA Luis  Quiroga, MD, MPH  Department of Surgery, Division of Plastic, Reconstructive, and Hand Surgery, West Virginia University School of Medicine, Morgantown, WV, USA David  Renton, MD Division of General Surgery, Ohio State University, Columbus, OH, USA Hannah Rinehardt, MD  Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Christina  Sanders, DO, MBA, FACS, FASMBS, FACOS  Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New  York at Buffalo, Buffalo, NY, USA Stefan Scholz, MD  Division of Pediatric General and Thoracic Surgery, Department of Surgery, University of Pittsburgh School of Medicine, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Keri A. Seymour, DO, MHSc  Department of Surgery, School of Medicine, Duke University, Durham, NC, USA Emanuel Shapera, MD  Department of Surgery, SHARP Grossmont Hospital, La Mesa, CA, USA

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Iswanto  Sucandy, MD, FACS  Department of Surgery, Advent Health Tampa, Tampa, FL, USA Palakorn Surakunprapha, MD  Division of Plastic and Reconstructive Surgery, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand Nova  Szoka, MD, FACS, FASMBS Department of Surgery, West Virginia University, Morgantown, WV, USA Elwin Tham, MD  Department of Surgery, West Virginia University, Morgantown, WV, USA Andrea Trinh  Department of Surgery, Methodist Dallas Medical Center, Dallas, TX, USA Acara Turner, MD  Department of Surgery, Division of Plastic, Reconstructive, and Hand Surgery, West Virginia University School of Medicine, Morgantown, WV, USA Cristiane M. Ueno, MD  Department of Plastic and Reconstructive Surgery, Ohio State University College of Medicine, Columbus, OH, USA Steven D. Wexner, MD, PhD (Hon)  Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA Andrew Williams, BS  West Virginia University School of Medicine, Morgantown, WV, USA Apinut  Wongkietkachorn, MD, PhD Division of Plastic and Reconstructive Surgery, Department of Surgery, Faculty of Medicine, Mae Fah Luang University, Chiang Rai, Thailand Supawich Wongkietkachorn, MD  Department of Surgery, Police General Hospital, Bangkok, Thailand Kerri  Woodberry, MD, MBA, FACS  Department of Surgery, Division of Plastic, Reconstructive, and Hand Surgery, West Virginia University School of Medicine, Morgantown, WV, USA

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Department of Surgery, Division of Plastic and Reconstructive Surgery, West Virginia University School of Medicine, Morgantown, WV, USA Gene Yang, MD  Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA David Zekan, MD  Department of Urology, West Virginia University, Morgantown, WV, USA

1

History and Science of Immunofluorescence Ludovica Baldari, Luigi Boni, and Elisa Cassinotti

Introduction The term fluorescence-guided surgery describes a medical technology based on real-time imaging intended to help and guide the surgeon during their operating practice. The first clinical use of fluorescence was in 1947, when it was used for identification of brain tumors during neurosurgery using the dye fluorescein. After the first experience, other applications have been reported in several surgical fields, but fluorescence-guided surgery has exponentially developed and spread only during the last years. Indeed, recently, many innovations in surgical technique and minimally invasive technologies with laparoscopic, endoscopic, and robotic approaches have greatly improved surgical practice. L. Baldari (*) Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy e-mail: [email protected] L. Boni · E. Cassinotti Department of General and Minimally Invasive Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy Department of Scienze Cliniche e delle Comunità, University of Milan, Milan, Italy e-mail: [email protected]; [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 N. Szoka et al. (eds.), The SAGES Manual of Fluorescence-Guided Surgery, https://doi.org/10.1007/978-3-031-40685-0_1

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Nevertheless, despite these constant advances, surgery still relies primarily on the surgeon’s vision and on white-light reflectance. The emerging field of fluorescent surgical imaging promises to be a powerful enhancement to improve surgical guidance. Among all chromophores and fluorophores that could work as probes in medical imaging techniques, near-infrared fluorescence imaging with indocyanine green (ICG) is emerging as the major contribution to intraoperative surgical decisions, and many different applications have already been described in literature. ICG is a dye used in medicine since the mid-1950s for a variety of diagnostic applications in cardiology and ophthalmology and to test the hepatic clearance. However, its fluorescent properties have only recently been applied to new minimally invasive surgical instrumentations. ICG has some peculiar features that promote its widespread use, like low incidence of adverse effects and very high toxic dose for the human body. Other fluorescent probes already approved for clinical use are methylene blue (MB), fluorescein sodium, and 5-aminolevulinic acid (5-ALA). Moreover, many probes are currently under clinical development. In addition, fluorescence-guided surgery appears to have a great potential to become a standard in everyday clinical practice due to its multiple different possible applications and its ease of employment.

History of Immunofluorescence  rom Semeiotics to Fluorescence-Guided Surgery F Through Medical Imaging In clinical practice, especially in surgery, the development of a new technology needs to meet these critical criteria: to represent a true clinical requirement, the possibility to solve an open issue, and the peculiar ability not to interfere with normal clinical ­workflow [1]. This is the reason why, before the end of the nineteenth century, the diagnostic and therapeutic process into the surgical field relied

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on the physician’s hands and eyes. In 1895, Wilhelm R ­ öntgen took the first known X-ray picture of his wife’s hand, accidentally discovering the X-ray [2]. Since this report, after many decades of improvements in medicine, there are few imaging techniques routinely employed in clinical practice that can be divided into two main segments: optical and radiological imaging [3]. Covering the 36% of the global market, radiological imaging includes X-ray, computed tomography (CT), ultrasound, magnetic resonance imaging (MRI), and positron emission tomography (PET), and only two of these (X-ray fluoroscopy and ultrasound) are used occasionally for image-guided surgery. Indeed, these techniques are mainly used for preoperative imaging that is fundamental to plan the surgery, but it can lead to misinterpretation during the procedure due to distortion of images and the time interval between imaging and surgery (e.g., in cancer patients) [4]. Nevertheless, optical imaging covers 64% of the global market, including endoscopy, microscopy, visual surgery, ophthalmic surgery, medical lasers, and robotics-based surgery. The fundamental of optical imaging is the use of light in the ultraviolet, visible, and near-infrared regions of the electromagnetic spectrum, allowing diagnosis and re-evaluation more frequently as the patient is not exposed to ionizing radiation. Moreover, through varying photon absorption and light scattering from different types of tissue, optical imaging can differentiate suspicious tumoral and healthy tissues, using multiple properties of soft tissue [5]. One of the main areas of optical imaging is fluorescence-­ guided surgery (FGS) in the field of intraoperative imaging techniques. Intraoperative imaging techniques have been developed to help the surgeon identify areas invisible to the naked eye. The main characteristic of an intraoperative imaging technique is the speed at which visual information is obtained. The term “fluorescence-guided surgery” describes a medical technology based on real-time imaging intended to help and guide the surgeons during their operating practice. In recent years, technological progress in body imaging and diagnostics has enhanced patient selection for surgical interventions. At the same time, surgery has advanced substantially to decrease patient morbidity and trauma through innovations in endoscopic, laparoscopic, and

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robotic technologies. Nevertheless, surgical practice is still based on anatomy as seen by the operating surgeon with white-light reflectance. This approach does not allow an accurate differentiation between different tissues: in the body, they appear as various shades of white to pink (bone, nerves, cartilage, fat, connective tissue, and muscle) or red to deep red (blood vessels and more easily visible organs such as the liver, kidney, and spleen), thus leading to potential ambiguity during surgical dissection. Furthermore, open-field surgery depends on the direct visualization of patient tissues, whereas in minimally invasive surgeries (i.e., microscopic, endoscopic, laparoscopic, and robotic surgery), patient’s tissues are visualized through an interface (viewed through the ocular eyepiece or using cameras and digital displays). For the minimally invasive surgical procedures, the added hardware that is necessary for fluorescence imaging can be fitted into existing instrumentation. The emerging field of fluorescent surgical imaging promises to be a powerful enhancement to traditional low-contrast white-light visualization, offering real-time highlighted delineation of complex anatomic structures. Improved visualization will lead to more complete removal of disease, decreased inadvertent injuries to vital structures, and improved identification for repair of damaged tissues [6]. In addition, working through an interface with cameras and instruments inserted into body cavities through narrow conduits has also sacrificed tactile feedback of directly working with tissue and dissection along tissue planes. Thus, a medical specialty that is traditionally dependent on touch becomes even more dependent on vision. Thus, enhancing the visual differences between tissues by using fluorescent probes based on structure or disease could be equated to color-coding the surgical field. This is the reason why FGS could represent a major contribution to intraoperative decision-­making during surgical procedures [7].

First Reports of Fluorescent Events The first description of fluorescence dates to 1560 and 1565 by Bernardino de Sahagún and Nicolás Monardes, respectively. They

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reported an early observation of fluorescence in the lignum nephriticum infusion that was derived from the wood of the following tree species: Pterocarpus indicus and Eysenhardtia polystachya. The chemical component emitting fluorescence was the matlaline, derived from the oxidation of wood flavonoids. In 1819 and 1822, mineralogists Edward D. Clarke and René Just Haüy described fluorescence in fluorites, respectively. The phenomenon was described for chlorophyll by Sir David Brewster in 1833 and for quinine by Sir John Herschel in 1845. In his 1852 article on “Refrangibility,” the British physicist and mathematician George Gabriel Stokes, noted for his studies of the behavior of viscous fluids and for Stokes’ theorem, described the ability of fluorspar and uranium glass to change invisible light beyond the violet end of the visible spectrum into blue light. This phenomenon was called “fluorescence.” The name derives from the mineral fluorite (calcium difluoride) that can contain traces of divalent europium that serves as the fluorescent activator to emit blue light. In a fundamental experiment, a prism was used to isolate ultraviolet radiation from sunlight and he observed blue light emitted by ethanol solution of quinine [8].

Preliminary Use of Fluorescence into Surgical Field The first clinical use of fluorescence was in 1947, when it was used for identification of brain tumors during neurosurgery using the dye fluorescein [9]. In 1953, Ray and Randall succeeded in detecting cancer cell in vaginal smears through a fluorescent staining. The rationale behind the research was the affinity of the basic fluorochrome dyes (berberine sulfate, acid fuchsin, and acridine) for nucleic acids. As neoplastic cells have an increase in total nucleic and ribonucleic acids, with an increase in protein synthesis, cancer cells were identified. A fluorescent microscope was used to evidence this finding [10]. In 1955, Peck and Mack investigated the affinity of hematoporphyrin for malignant tissue and its capability to evidence the biliary anatomy after biliary excretion through its fluorescent properties. They used different spectra of the hematoporphyrin to

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visualize malignant tumors and bile ducts. Today, hematoporphyrin is used as an endobronchial tumor indicator to facilitate the bronchoscopic localization of early squamous cell carcinoma of the central tracheobronchial tree [11, 12]. In 1963, Acherman and McFee studied tetracycline fluorescence in benign and malignant tissues. Tetracycline has fluorescent properties in ultraviolet light allowing its detection through yellow color into tissue. The authors demonstrated that few minutes after parenteral administration, the drug is distributed to all body tissues apart from the central nervous system, with the highest concentrations in liver, kidneys, and bones. In 1957 Ral et al., during a study on the effects of fluorescent riboflavin antagonist on breast cancer metastases, observed the presence of fluorescent material in tumor tissue of patients treated with tetracycline some weeks before. Klinger and Katz reported that oral administration of tetracycline for 5 days followed by gastric washing for exfoliative cytology after 36 h and examination of aspirate residue under ultraviolet light could allow the visualization of cancerous cells. Fluorescence was seen in 17 of 18 patients with stomach cancer and was not noted on 42 patients without cancer [13, 14]. In 1965, Whitmore et  al. performed ultraviolet light cystoscopy after administration of tetracycline, concluding that this method has higher sensibility to evidence tumor if compared to light cystoscopy. It could identify grade III tumor in patients with positive urinary sediments, but negative visible light cystoscopy. There was no relation between fluorescence occurrence and the grade of histologic malignancy or bladder carcinoma type. Ultraviolet cystoscopy can give a valid guidance for biopsy, facilitating early detection of recurrence in patient with persistent tumor cells in urinary sediments but no tumor at visible light cystoscopy after treatment for bladder cancer [15]. It was only in 1966 that fluorescence was used to evaluate perfusion. Tetracycline was used for evaluation of ischemic changes in renal transplantation. After this evidence, renal spectroscopy was defined as a noninvasive method to determine organ viability in renal ischemia and reperfusion. This conclusion was achieved through a study of fluorescence spectroscopy that used histologic evidence to evaluate ischemic injury and organ viability. Authors

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stated that there is a strong correlation between fluorescence spectroscopy and histologic changes only in the reperfusion phase after renal ischemia. Thus, the described technique was unable to define the viability of organs before transplantation [16, 17]. After these results, fluorescence was tested in different fields as early detection of brain and rynolaringologic tumors. Nessel tested tetracycline fluorescence in rhinolaryngologic malignant tumors’ surgery, and Golghahn in brain tumors [18, 19]. After studies on renal ischemic changes in transplant surgery, fluorescence was evaluated in cardiac surgery. There were published studies on the use of fluorescence for defining the degree of revascularization of the heart in surgical treatment of experimental cardiac ischemia and tetracycline fluorescence in experimental necrotizing cardiopathies and in the macroscopic delimitation of experimental acute myocardial ischemia before and after revascularization [20, 21]. This field of research has been in constant development since the 1950s, leading to three Nobel Prizes in Chemistry for the organic chemist and marine biologist Osamu Shimomura, the scientist Martin Chalfie, and the biochemist Roger Yonchien Tsien for the discovery and development of green fluorescent protein in 2008 [8]. The main field of current research and clinical applications of fluorescence in surgery will be extensively described in the following chapters of this book.

Basic Principles of Fluorescence Fluorescence is the emission of electromagnetic radiation at one wavelength, especially of visible light, stimulated in a substance after absorption of incident radiation, at a different wavelength, which ceases once the incident radiation stops. From a chemical point of view, the light absorbed by an atom or a molecule causes the transition of an electron from the ground state to a certain excited state. After a brief period (nanosecond scale), the electron relaxes to its ground state, emitting part of this energy at a different wavelength. This energy is emitted in the form of photons and

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8 f µ1/l Infrared

Ultraviolet

Visible 0

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Fig. 1.1  Electromagnetic spectrum and its relation to visible, ultraviolet and infrared light: wavelength (λ), frequency (f) (nm nanometer)

it is lower, thus corresponding to longer wavelength, than the absorbed photons (and energy). The wavelengths associated with fluorescence and energy absorption are in the range of 200–1000 nm and can be divided as follows: • Ultraviolet range: 200–400 nm. • Visible range: 400–600. • Near-infrared (NIR) range: 600–1000 nm (Fig. 1.1).

Fluorophores Molecules that emit fluorescence are called “fluorophores.” Their chemical structure is usually made of merged or conjugated aromatic groups. There are several fluorophores available: organic molecules, minerals, nanoparticle, and transition complex metals. To be used in vivo, fluorophores should demonstrate fluorescence when stimulated by different wavelength light sources and should also have good solubility and photophysical characteristics (brightness, peak excitation, and photostability). Owing to their hydrophobicity, fluorophores often demonstrate poor solubility and aggregation in solution, which can lead to changes in their excitation and emission ranges, as well as quenching of fluorescence [22–24]. When using a fluorophore, four parameters have to be known in order to obtain information of fluorescent signal into the microenvironment:

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• Fluorescence intensity that changes according to excitation energy. • Emission wavelength: emission energy is lower than the excitation one, with emission wavelength that is higher than the excitation one. • Fluorescence lifetime: the mean time the fluorophore spends into the excited state before photon emission. • Fluorescence polarization: describes the polarization of the emission compared to the absorption. It gives information about viscosity of the medium and molecular size. Fluorescence has been exploited in several areas, and, as aforementioned, during the last decades, it reached the medical and surgical field, giving birth, with the development of new technologies, to fluorescence-guided surgery. If this specific molecule allows to study and gives information about the structure and/or a system, it is named “fluorescent probe” [8, 25, 26]. As aforementioned, fluorescence-guided surgery needs fluorescent probes to be performed.

Chromophores in Surgical Practice A chromophore can basically be defined as an “optically active” substance. Chromophore-containing molecules are widely used in conventional surgical practice because of their capability to enhance human vision; their application is demonstrated across several medical specialties, ranging from skin marking ink and sentinel lymph node biopsy (SLNB) to methylene blue for urinary tract lesions [27]. Surgeons increasingly demand for real-time sensory input to achieve a more accurate identification of tissues during their practice. Enhanced visual differentiation of anatomical structures becomes even more important, especially when considering new minimally invasive surgical technology where there is a loss of tactile feedback and everything the surgeon sees is “filtered” from the screen.

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In a conventional operating setting, even if the use of some kind of chromophore in medical practice is already established, surgeons have always relied on which is visible to the naked eye (390–700 nm) [28]. While this principle contributes to the mainstay of conventional surgery, it suffers from several drawbacks including multiple light shadowing, dependence on the operating surgeon, and experience [29]. Furthermore, the unmet clinical need in surgery stems from the fact that visible light cannot penetrate blood and tissue more than a few hundred microns, due to high photon attenuation from absorbance and scatter. Thus, when a surgeon looks at the surgical field, he only sees surface features. The implications of this are significant since there are over 40 million surgical procedures performed in the United States (US) each year, and even small improvements in outcome, or reductions in morbidity, will affect large patient populations [1]. FGS can obtain a fundamental role in preservation of normal tissues such as lymphatics, ureters, bile ducts, and blood vessels that are visualizable using untargeted tracers such as ICG [7]. The need to find new applications for chromophores in diagnostics and operative settings led to the development of specific dyes and probes that could be seen in target tissues beyond the visual spectrum, through the use of special light sources ranging from ultraviolet (UV) to near-infrared (NIR) wavelengths.

Fluorescent Probes Fluorescent probes are contrast agents able to enhance a specific structure of tissue from surrounding ones. Based on their fluorescence emission spectra, clinically evaluated dyes can be separated into three groups. The first group includes probes emitting fluorescence in the visible part of the light spectrum (400–650 nm) with fluorescein sodium being one of the most widely used visible dye in clinical care today. The second group consists of dyes emit-

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ting in the far-red region of the light spectrum (650–750  nm). Here, an interesting development has been the clinical introduction of the relatively bright cyanine dye named Cy5. The last group consists of near-infrared emitting cyanine dyes (750– 1000 nm) such as indocyanine green (ICG) [8, 30]. There are two main types of fluorescent probes: intrinsic and extrinsic.

Intrinsic Probes Intrinsic probes have the intrinsic property to become fluorescent in their native form. They can be found in nature components and into the human body. The main advantages are that they do not need any external probe to fluoresce, and they need less regulation in order to be used in clinical practice. The main disadvantage is that the resulting fluorescence intensity is low, ending with low contrast between target structures and surrounding tissues. Indeed, the penetration depth is low and many other endogenous fluorophores can fluoresce under the same condition. Thus, to date, endogenous fluorophores are not currently used in fluorescence-­ guided surgery, but only as research topic [31]. However, they seem to have high potential, so they will be used probably in clinical practice in the future. The most used endogenous fluorophores are described below (Table 1.1): Table 1.1  Characteristics of the main endogenous fluorophores Fluorophore Collagen Elastin NADH/NADPH FAD Lipofuscin

Absorption peak (nm) 325 290, 325 340 450 340–395

Emission peak (nm) 400 340, 400 450 535 430–460

Average lifetime (ns) 5.3 2.3 0.4 2.3–4.7 1.34

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• Collagen, a structural protein of connective tissue, and elastin, a protein of the extracellular matrix. These proteins fluoresce at low wavelength, so they can be used in superficial sites. For example, they can be used to identify necrosis of bones, allowing a precise removal from healthy tissue [4]. • Nicotinamide adenine dinucleotide (NADH), a key factor in cellular energy metabolism, nicotinamide adenine dinucleotide phosphate (NADPH), and flavin adenine dinucleotide (FAD). These two species, i.e., NADH and NADPH, are spectrally identically fluorescing at the same wavelength, with peak emission at ∼450 nm, so they cannot be distinguished in living cells. FAD is involved in cellular energy metabolism too and fluoresce with peak emission at ∼535 nm. This different peak emission allows a simultaneous use of fluorescent properties of NADH/NADPH and FAD. For example, they can be used for intraoperative tumor margin analysis [4]. • Lipofuscin, which accumulates in granules in retinal pigment epithelium with age, especially in patients with visual disease, has a peak emission at ∼578 nm and can be used to study eye surface [32].

Extrinsic Probes Extrinsic probes are molecules designed to fluoresce under specific conditions in order to obtain a fluorescent signal that it would not exist otherwise. Compared to intrinsic probes, the main advantages of the extrinsic ones are better fluorescent properties, like intensity, and major control in choosing the structure where the probe has to concentrate or be labeled to gain the specific signal. They can be distinguished based on the wavelength they require to be excited and seen and can be classified as “targeted” and “untargeted” [7]. In current clinical practice, non-targeted fluorophores are the most common. Usually, the choice of a fluorophore must take into consideration the following specifics [1, 6, 7]:

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• • • •

Dose (quantity needed to achieve the desired effect). Time between administration and visualization. Pharmacodynamics. Way of administration (e.g., systemic vs. local).

Severe regulatory requirements are necessary to have a fluorescent dye approved for clinical use. Thus, some probes are already available on the market, while some others are still being tested and developed.

 urrently Approved Extrinsic Probes C Due to multiple possible applications, many groups around the world are developing novel fluorophores and targeted fluorophores. Nevertheless, the reality is that first-in-human testing of a new chemical entity has a minimum lag of about 2 years, and commercial availability of a new chemical entity has a minimum lag of 2–5 years. For the foreseeable future, there are only four molecules approved for by the FDA (Food and Drug Administration) and thus clinically available for study: fluorescein sodium, methylene blue (MB), indocyanine green (ICG), and 5-­ aminolevulinic acid (5-ALA). Interestingly, methylene blue (MB) and indocyanine have been used for the last decades as visible dyes, and for this reason, there is a large amount of clinical data regarding their safety when used at millimolar concentrations [1] (Table 1.2). All these approved fluorescent probes are untargeted.

Table 1.2  Characteristics of the main extrinsic probes approved by FDA Fluorophore Fluorescein sodium Methylene blue Indocyanine green 5-ALA

Absorption peak (nm) 490 665 780 410

Emission peak (nm) 510 685 830 630

Average lifetime (ns) 4.0 0.6 0.16 15

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• Fluorescein sodium. It is a manufactured organic compound that is FDA approved with peak excitation at ∼ 490 nm and peak relaxation at ∼ 510 nm [4]. The first clinical application of fluorescein sodium was for the identification of brain tumor in 1948. It is still used for the same purpose in neurosurgery and also widely used as a fluorescent tracer for many other applications, like in ophthalmology and optometry (retinal angiography and angioscopy), detection of oral dysplasia and cancer, and detection of tumors of peripheral nerve sheath. Fluorescein sodium is the designated fluorophore to obtain images through confocal microscopy and its related applications, such as flow cytometry [33]. The relative low cost and the possibility to visualize fluorescein sodium with the naked eye are advantages if compared to other probes. The main disadvantage is that it fluoresces within the visible spectrum, overlapping with endogenous fluorophores. [4]. • Methylene blue. Compared to visible spectrum, the near-­ infrared (NIR) range is more favorable in surgery, as light is less absorbed by tissue and allows greater penetration depth. One clinically approved dye with beneficial properties in the visible and NIR spectrum is methylene blue. It is a hydrophilic phenothiazine derivative with peak excitation at ∼665 nm and emission at ∼685 [34]. Its fluorescent performance is inferior to the ICG one (below described), due to a lower quantic energy (ratio between the number of electrons emitted and the number of incident photons), and exhibits an extinction ­coefficient and QY far below those of the indocyanines [1] (Figs. 1.2 and 1.3). It is partially excreted through urine and, for this reason, could be useful for ureteral visualization in surgery [35]. Due to the unique biodistribution and fluorescent properties of MB, its application in identifying vital structures, such as assessment of cardiac perfusion and detection of several types of tumors, including neuroendocrine tumors, fibrous pancreatic tumors, paragangliomas, and parathyroid adenomas, sentinel lymph node mapping, has been demonstrated by several inves-

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Fig. 1.2  Chemical composition of methylene blue 1.0

Absorption (Normalized)

0.8

0.6

0.4

0.2

0 200

300

400

500

600

700

Wavelength (nm)

Fig. 1.3  Absorbance spectrum of methylene blue

tigators. However, the tumor-targeting properties of methylene blue remain poorly understood and based on small studies and reports. Moreover, methylene blue has a low fluorescence yield and no functional group for adding ligands [4]. • Indocyanine green. It is a water-soluble tricarbocynanine dye that has been used clinically for over 50 years for hepatic clearance, cardiovascular function testing, and retinal angiography on the basis of its dark green color. ICG dye was developed for

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near-infrared photography by the Kodak Research Laboratories in 1955 and was approved for clinical use already in 1956. However, it took over 10 years before ICG was used for angiography. It has been used for retinal angiography since the early 1970s [36]. Indocyanine green is a negatively charged ion that belongs to the large family of cyanine dyes, having a molecular weight of 751.4 Da. Dry ICG is stable at room temperature. In aqueous solutions, ICG molecules tend to aggregate, which influences their optical properties. The aggregation depends on concentration and time. The spectral stabilization is fastest when ICG is dissolved in distilled water, and thus some authors do not recommend adding isotonic saline and/or albumin to the injectate, when fast spectral stability is essential, for example, when using ICG for quantitative purposes. IGC is hydrophobic and, thus, it frequently bounds to proteins in plasma (especially albumin), which confines ICG to the intravascular space and makes it especially suited for angiographic applications [26, 27]. ICG­based angiography and lymphography have been used in a variety of clinical indications, such as perfusion­based imaging of the liver and blood vessels of the eye and assessment of lymphatic vessel drainage. The important property of fast binding to plasma proteins, especially lipoproteins, makes repeated intraoperative applications of ICG possible. The binding to plasma proteins does not seem to alter protein structures, which is one sign of nontoxicity. Binding to blood proteins also shifts slowly, taking several minutes, the absorption peak at 780 nm toward longer wavelengths, to 805 nm. The absorption peak maximum was observed at 810 nm in the epidermal cell cultures and at 805–810  nm in the human skin in  vivo (Figs. 1.4 and 1.5). ICG does not have any known metabolites, and it is quickly extracted by the liver into bile juice. The transport is done by a protein called glutathione S-transferase without modification. The protein spectra of different liver diseases also affect ICG protein binding in blood. It has a quick clearance rate of 18–24% per minute by the liver, which is the result of both the

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Fig. 1.4  Chemical composition of indocyanine green

Absorption / Emission (Normalized)

1.0

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800

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1000

Wavelength (nm)

Fig. 1.5 Absorbance and fluorescence-emission spectra of indocyanine green. Continuous and dotted lines show absorbance and emission spectra respectively

compound’s confinement to the intravascular space and that the decomposition products of ICG are not metabolites. The dye is cleared from the system exponentially in the first 10–20  min after application, with a half-life of generally

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3–4 min depending on the vascularization of the organ of interest [26, 27, 36]. The typical dye concentrations used for in vivo retinal angiography are in the range of 20–25 mg/mL of ICG applied by injection into a peripheral arm vein. For studies of hepatic function, an intravenous injection dose is calculated on the basis of 0.5 mg/kg of body weight. In cardiac output and blood volume monitoring, the total dose of dye injected should be kept below 2 mg/kg. Peculiar feature is the low toxicity (LD50 after single IV dose of 50–80 mg/kg for animals). No significant toxic effects have been observed in humans with the high dose of 5  mg/kg of body weight. ICG for injection contains sodium iodide and should be used with caution in patients who have a history of allergy to iodides because of the risk of anaphylaxis. ICG was not found to be mutagenic in the tests performed. No studies for reproduction, teratogenicity, or carcinogenic properties in animals are available, but decades of experience in humans have not revealed any incidence of these properties. To date, ICG is the first and only clinically approved fluorophore that displays NIR fluorescence. Because ICG has no functional groups for conjugation to targeting moieties for molecular imaging application, it is a nonspecific contrast agent. The commercially available instrumentation used for ICG detection is adjusted for the characteristics that ICG displays in plasma (peak excitation wavelength of 807  nm and peak emission wavelength of 822 nm) [36, 37]. • 5-aminolevulinic acid. 5-ALA is an amino acid that acts as a fluorophore processed by high metabolic active cells. Indeed, it is a precursor of protoporphyrin IX that is involved in the pathway of heme synthesis. After 5-ALA administration, protoporphyrin IX accumulates in malignant glioma tissue, which became fluorescent, due to an abnormality in porphyrin metabolism.

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Fig. 1.6  Chemical composition of 5-aminolevulinic acid

It exhibits a fluorescence absorption peak of 405 nm, and an emission peak in the red visible light range (635 nm), permitting fluorescence imaging on the surface of tissues and in a depth range of millimeters. This fluorescence spectrum outside the NIR window is a disadvantage for surgical application, but it has minimum toxicity and 5-ALA is naturally present in the body (Figs. 1.6 and 1.7). Approved in 2017 by FDA, it is used mainly for FGS for guided ablation of malignant glioblastoma-based. In addition, 5­ALA has also been used in clinical settings for the photodynamic detection and photodynamic therapy of many superficial skin lesions, and its use is being investigated in several cancer types [4, 38]. The main limit of extrinsic probes is the limited approved number for clinical use. The approval process is long, because a good fluorescent probe should have good fluorescent properties, low toxicity, great quantum yield, and short half-life. Indeed, depending on the fluorophore uptake from the target tissue, the greater the quantum yield is, the smaller the dose to achieve effectiveness. Moreover, short half-life implicates rapid clearance so the possibility to repeat fluorophore administration for further intraoperative evaluation.

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20 1.0

Intensity

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0.2 0 200

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Fig. 1.7  Absorbance and fluorescence-emission spectra of Protoporphyrin IX.  Continuous and dotted lines show absorbance and emission spectra respectively

 xtrinsic Probes Under Clinical Development E Even if the approval process is long and difficult, there is high interest in fluorophore development for clinical use. A recent review reported that a total of 85 trial have been registered to test 39 new contrast agents for fluorescence-guided surgery. Some of these probes under development utilize target like antibodies or peptides to obtain highly specific fluorescent signal. For example, optically active probes can specifically label intra- and extracellular biomarkers of cancer. Targeted fluorophores actually under development aim mainly to identify cancer cells in order to diagnose tumor early and to verify that tumor dissection is complete. Other untargeted probes generate fluorescent signal through enzymatic process. Others have fluorescent properties themselves [4, 39]. Some of these probes for fluorescence-guided surgery have reached phase III clinical trials: • SGM-101. It is a target antibody for carcinoembryonic antigen (CEA) linked with a NIR fluorophores. It has been tested in colorectal tumors, showing high specificity in primary tumor tissue and in metastases [40].

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• BLZ-100. It is a chlorotoxin peptide linked to ICG, with affinity for metalloprotease 2. It has been studied for pediatric ­central nervous system tumor, showing specificity for tumor tissue and correlation with fluorophore dose and cancer grade [41]. • OTL38. It is composed of folic acid and NIR fluorophore S0456. It has demonstrated high sensitivity for ovarian cancer tissue [42]. Several other probes under development are in phase II or phase I clinical trials. Some of these contrast agents are BBN-­ IRDye800CW for brain cancer, fluorescein-conjugated Wisteria floribunda for colon cancer, and EC17 for renal carcinoma. Clinically approved fluorescence imaging systems are compatible with FDA-approved contrast agents. Thus, most of the systems are set for ICG, with excitation and emission wavelength around 800  nm. Few imaging systems have capability for fluorescein and 5-ALA fluorescence, and only two systems have the possibility to perform fluorescence surgery with methylene blue in the spectrum of 700 nm. As a result, because fluorescence is centered around 800 nm, the most used fluorophore for contrast agents under development is the IRDye800CW. Thus, there is a gap between fluorescent properties of new contrast agents and imaging possibility with approved imaging systems [4].

Clinical Imaging Systems Fluorophores with excitation and emission spectra in the near­ infrared wavelength range (700–900 nm) have attracted the most attention owing to their improved depth penetration range compared with fluorophores that emit electromagnetic radiation of shorter wavelengths. Within this NIR window, the absorption of most biomolecules (i.e., deoxyhemoglobin, oxyhemoglobin, water, and lipid) reaches minimal levels, and scattering and autofluorescence are relatively low. Since NIR fluorescent light is essentially invisible to the human eye, special imaging systems

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are required to excite the NIR fluorophores within the surgical field and to collect emitted photons. Well-designed NIR fluorophores are needed to highlight the specific structures desired by the surgeon. The commercial development of these agents for clinical application has synergized with concurrent improvements in detection instrumentation and software [1]. ICG becomes fluorescent once excited with NIR light or with a dedicated laser beam. The fluorescence can be detected using specific scopes and cameras and then transmitted to a standard monitor allowing identification of anatomical structures where the dye is present (i.e., biliary ducts, vessels, lymph nodes, etc.) [43] (Fig. 1.8). ICG is the only NIR fluorophore employed to date for human use. As described previously, it had widespread uses in hepatic, cardiac, and ophthalmologic studies, and its use is recently reported in analyzing tissue perfusion and identifying lymph nodes in cancer patients. It has several clinically excellent properties, which has been thoroughly verified during its long clinical use [36]: • Patient safety (nontoxic, nonionizing). • Ideal for angiography because it binds efficiently to blood lipoproteins and does not leak from circulation; ideal for bile duct study because it is excreted selectively through the bile. • Short lifetime in blood circulation allowing repeated applications. • Good signal-to-background ratio (SBR): there is not much NIR autofluorescence in tissue where the exogenous dye is not present. • Deep imaging with possibility to see beyond the surface, at a depth of several millimeters. • Simple and relatively cheap imaging devices.

Components of Fluorescence-Based Surgical System Fluorescence technology used in surgical system is based on methodology already defined in fluorescence microscopy and spectroscopy [44]. The system is made of an excitation source, a

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Fluorophore

filter > 760 nm 800 nm

CCD Camera

0

nm

L so igh ur t ce

76

Fig. 1.8  Operating principle of Fluorescence Guided Surgery (FGS)

fluorescent probe (described above), filters, and fluorescent detector.

Excitation Source The excitation source to obtain a fluorescent signal is a light that can be generated by xenon lamps, light emitting diodes (LEDs), and laser diodes. Even if lamps are flexible, allowing a wide range of wavelength, they are not the ideal source as they produce heat, requiring a warm-up period, and deteriorate with use with a ­consequent decrease of brightness. LEDs are more

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diffused. If compared to xenon lamps, LEDs have longer lifetimes, do not need warm up period, have lower consumption, and have a narrow bandwidth. Laser diodes have a narrower wavelength and higher intensity compared with the other two sources. Laser source is more expensive than LED ones, so they are less diffused [4].

 luorescence System Filters F Excitation and emission filters are necessary to select wavelengths and unwanted signal. For example, emission filters can be used to narrow the fluorescent signal collected to the spectrum of interest. Emission filters’ features should be clearly defined and balanced, as a large band allows higher intensity of the signal but less specificity resulting in lower contrast between the target and the background. Moreover, the filter has to be chosen according to the Stokes shift of the fluorophore, that is the difference (in wavelength or frequency units) between positions of the band maxima of the absorption and emission spectra of the same electronic transition [4].  luorescence System Detectors F The aim of the detector is to quantify the fluorescence of the single photons according to quantum efficiency, that is the ability to convert the incident light to excited electron, and internal gain, that is the ability to amplify the signal in a large electrical signal. To date, several systems are currently used to detect photons in surgical field: • Photomultiplier tubes absorb the incident photons and produce electrons to obtain the signal. • Microchannel plate photomultipliers absorb the incident photons and produce electron with an amplification of the signal and improved time resolution of the detection system. • Charge-coupled devices are made of pixel array that produce a signal proportional to exposure time of incident light, resulting in high sensitivity. • Single photon avalanche photodiode generates current quickly

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after photon absorption, thanks to a multiplexed pixel array. The main advantage is the higher quantum efficiency. Each of these detectors has advantages and disadvantages, and even if single photon avalanche photodiode has high potential for fluorescence lifetime use, photomultiplier tubes and charge-­ coupled devices are still currently used [4].

 urrently Available Devices for Fluorescence-­ C Guided Surgery Nowadays, a growing number of companies are developing new systems for FGS. These systems that are suitable for both near-­ infrared (NIR) fluorescence and white-light (WL) imaging, integrating the aforementioned technology, available for both open and minimally invasive surgery. Each system differs from others on some key features: • The “exciting” light source type (neon light, LED, or laser beam). • The system of signal detection. • The wavelength emitted and captured. • The optimal distance to visualize fluorescence signal. • The strength of SBR. • The possibility of directly overlaying the NIR images to the WL ones. The different features that characterize each device (field of vision, zoom capability, type of light source, NIR wavelength emitted and captured, etc.) will have an impact on system performance during surgery. During surgical procedures, the alternate exposure from WL to NIR light (ICG mode) is used to identify anatomical structures, blood perfusion, and other details. The fluorescence imaging systems allow to obtain fluorescent images in real-time setting. They are quite unexpensive, if compared to some other technological equipment widely adopted in surgery [45].

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Table 1.3 reports some of the most widely adopted devices both for conventional and minimally invasive/robotic surgery (Table 1.3).

Table 1.3  Some of the most widely adopted NIR imaging systems both for conventional and minimally invasive/robotic fluorescence-guided surgery Imaging system Stryker

1688 advanced imaging modalities Pinpoint with SPY-PHI

Karl Storz 1 S™

Image 1S™

Image 1S™ Rubina™

Image resolution 4k

Visualization Use mode Laparoscopic – Green overlay mode – SPY-ENV mode – SPY-contrast – IRIS Full HD Open – Green overlay mode – Color-­ segmented fluorescence mode – SPY-­ fluorescence mode HD xenon Laparoscopic – Optical light illumination and source contrastenhanced modality – No overlay mode 4k and 3D Laparoscopic – Overlay mode Laser-free LED light source

Arthrex

Synergy ID System

4k

Da Vinci Surgical System (Intuitive)

Firefly 3D camera system integrated LED light into Da Vinci Si and Xi

– Intensity map

– Monochromatic Laparoscopic – Overlay mode – Monochromatic Robotic – Normal imaging and fluorescent modes – No overlay mode

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Conclusion In conclusion, since its first clinical application in surgery, fluorescence underwent huge development and spread among specialties. Among all the fluorophores, indocyanine green is the most diffused, thanks to its peculiar features that promote its widespread. Many probes are currently under clinical development and will be on the market soon. A growing number of companies are developing systems for fluorescence-guided surgery. This imaging system is in constant evolution with many features like overlay visualization and the second near-infrared window (1000–1700  nm), enhancing the power and increasing applications of this technology.

References 1. Gioux S, Choi HS, Frangioni JV. Image-guided surgery using invisible near-infrared light: fundamentals of clinical translation. Mol Imaging. 2010;9(5):237–55. 2. Howell JD. Early clinical use of the x-ray. Trans Am Clin Climatol Assoc. 2016;127:341–9. 3. Pogue BW.  Optics of medical imaging: optics plays dominant role in medical imaging market. In: SPIE professional, 2018. p. 6–8. 4. Stewart HL, Birch DJS.  Fluorescence guided surgery. Methods Appl Fluoresc. 2021;9:4. 5. National Research Council. Medical optical imaging mathematics and physics of emerging biomedical imaging. Washington DC: National Academy Press; 1996. https://doi.org/10.17226/5066. 6. Orosco RK, Tsien RY, Nguyen QT.  Fluorescence imaging in surgery. IEEE Rev Biomed Eng. 2013;6:178–87. 7. Nguyen QT, Tsien RY. Fluorescence-guided surgery with live molecular navigation--a new cutting edge. Nat Rev Cancer 2013;13(9): 653–662. 8. Dip FD, Ishizawa T, Kodudo N, Rosenthal RJ. Fluorescence imaging for surgeons concepts and applications. Basel: Springer; 2015. p.  3–23. ISBN: 978-3-319-35213-8. 9. Moore GE. Fluorescein as an agent in the differentiation of normal and malignant tissues. Science. 1947;106:130–1. 10. Lay CL, Randall LM. Fluorescent staining for detection of cancer cells in vaginal smears. Surg Forum. 1953:321–7.

28

L. Baldari et al.

11. Raymond J, Lanzafame MD, David W, Rogers BS, John O, Nairn MS, et al. Hematoporphyrin derivative fluorescence: photographic techniques for the localization of malignant tissue. Lasers Surg Med. 1986;6(3):328– 35. 12. Ahlquist RE Jr, Figge FH. Fluorescence of the extrahepatic biliary system following parenteral hematoporphyrin administration. Surg Forum. 1956;6:356–8. 13. Ackermann NB, Mc Fee AS.  Tetracycline fluorescence in benign and malignant tissues. Surgery. 1963;53:247–52. 14. Sandlow LJ, Allen HA. The use of tetracycline fluorescence in the detection of gastric malignancy. Ann Intern Med. 1963;58(3):409–13. 15. Whitmore WF Jr, Bush IM. Ultraviolet cystoscopy in patients with bladder cancer. Trans Am Assoc Genitourin Surg. 1965;57:149–55. 16. Málek P, Kolc J, Pultr V, Zástava V. Tetracycline fluorescence test in evaluation of ischemic changes in kidney transplantations. Rozhl Chir. 1966;45(4):252–6. 17. Cassini MF, da Costa MM. Fluorescence spectroscopy in renal ischemia and reperfusion: noninvasive evaluation of organ viability. Transplant Proc. 2013;45(5):1715–9. 18. Nessel E, Wiggermann W. The tetracycline fluorescence test in surgery of malignant tumors; rhinolaryngologic experiences. HNO. 1965;13(12):346–9. 19. Goldhahn WE.  Fluorescence studies of brain tumors. Beitr Neurochir. 1966;13:126–9. 20. Khutsishili TS, Milaeva MA. The use of the fluorescent method for determining the degree of revascularization of the heart in the surgical treatment of experimental cardiac ischemia. Grudn Khir. 1965;7(6):11–2. Russian. 21. Loisance D, Sadony V. Value of fluorescence in the macroscopic delimitation of experimental acute myocardial ischemia before and after revascularization. Arch Mal Coeur Vaiss 1973;66(6):701–707. 22. Zhang RR, Schroeder AB, Grudzinski JJ, Rosenthal EL, Warram JM, Pinchuk AN, et  al. Beyond the margins: real-time detection of cancer using targeted fluorophores. Nat Rev Clin Oncol. 2017;14(6):347–64. 23. Mordon S, Devoisselle JM, Soulie-Begu S, Desmettre T.  Indocyanine green: physicochemical factors affecting its fluorescence in  vivo. Microvasc Res. 1998;55:146–52. 24. Desmettre T, Devoisselle JM, Mordon S.  Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Surv Ophthalmol. 2000;45:15–27. 25. Valeur B, Berberan-Santos MN. Molecular fluorescence: principles and applications. Weinheim: Wiley-VCH; 2012. ISBN: 978-3-527-32837-6. 26. Lakowicz JR.  Principles of fluorescence spectroscopy. New  York, NY: Springer; 2010. ISBN: 978-1-4615-7658-7.

1  History and Science of Immunofluorescence

29

27. Azzopardi EA, Owens SE, Murison M, Rees D, Anne Sawhney M, Francis LW, et al. Chromophores in operative surgery: current practice and rationalized development. J Control Release. 2017;249:123–30. 28. Rashid A, Warnakulasuriya S. The use of light-based (optical) detection systems as adjuncts in the detection of oral cancer and oral potentially malignant disorders: a systematic review. J Oral Pathol Med. 2015;44(5):307–28. 29. de Boer E, Harlaar NJ, Taruttis A, Nagengast WB, Rosenthal EL, Ntziachristos V, van Dam GM. Optical innovations in surgery. Br J Surg. 2015;102(2):e56–72. 30. Fernandez-Suarez M, Ting AY.  Fluorescent probes for super-resolution imaging in living cells. Nat Rev Mol Cell Biol. 2008;9(12):929–43. 31. Mondal SB, et  al. Real-time fluorescence image-guided oncologic surgery. Adv Cancer Res. 2014;124:171–211. 32. Marmorstein AD, Marmorstein LY, Sakaguchi H, Hollyfield JG. Spectral profiling of autofluorescence associated with lipofuscin, Bruch’s membrane, and sub-RPE deposits in normal and AMD eyes. Invest Ophthalmol Vis Sci. 2002;43(7):2435–41. 33. Shin D, Vigneswaran N, Gillenwater A, Richards-Kortum R. Advances in fluorescence imaging techniques to detect oral cancer and its precursors. Future Oncol. 2010;6:1143–54. 34. Selvam S, Sarkar I. Bile salt induced solubilization of methylene blue: study on methylene blue fluorescence properties and molecular mechanics calculation. J Pharm Anal. 2017;7:71–5. 35. Matsui A, Tanaka E, Choi HS, Kianzad V, Gioux S, Lomnes SJ, Frangioni JV.  Real-time, near-infrared, fluorescence-guided identification of the ureters using methylene blue. Surgery. 2010;148:78–86. 36. Alander JT, Kaartinen I, Laakso A, Pätilä T, Spillmann T, Tuchin VV, et al. A review of indocyanine green fluorescent imaging in surgery. Int J Biomed Imaging. 2012;2012:940585. 37. Schaafsma BE, Mieog JS, Hutteman M, vad der Vorst JR, Kuppen PJ, Lowik CW, et al. The clinical use of indocyanine green as a near-infrared fluorescent contrast agent for image-guided oncologic surgery. J Surg Oncol. 2011;104:323–32. 38. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ.  Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401. 39. Staderini M, Megia-Fernandez A, Dhaliwal K, Bradley M. Peptides for optical medical imaging and steps towards therapy. Bioorg Med Chem. 2018;26:2816–26. 40. Hoogstins CES, Boogerd LSF, Sibinga Mulder BG, Mieog JSD, Swijnenburg RJ, van de Velde CJH, et  al. Image-guided surgery in patients with pancreatic cancer: first results of a clinical trial using SGM-

30

L. Baldari et al.

101, a novel carcinoembryonic antigen-targeting, near-infrared fluorescent agent. Ann Surg Oncol. 2018;25:3350–7. 41. Patil CG, Walker DG, Miller DM, Butte P, Morrison B, Kittle DS, et al. Phase 1 safety, pharmacokinetics, and fluorescence imaging study of Tozuleristide (BLZ-100) in adults with newly diagnosed or recurrent gliomas. Neurosurgery. 2019;85:E641–9. 42. Randall LM, Wenham RM, Low PS, Dowdy SC, Tanyi JL. A phase II, multicenter, open-label trial of OTL38 injection for the intra-operative imaging of folate receptor-alpha positive ovarian cancer. Gynecol Oncol. 2019;155:63–8. 43. Luo S, Zhang E, Su Y, Cheng T, Shi C. A review of NIR dyes in cancer targeting and imaging. Biomaterials. 2011;32:7127–38. 44. Engelborghs Y, Visser AJWG.  Fluorescence spectroscopy and microscopy: methods and protocols. Methods Mol Biol. 2014. https://doi. org/10.1007/978-­1-­62703-­649-­8. 45. Sevick-Muraca EM, Houston JP, Gurfinkel M.  Fluorescence-enhanced, nearinfrared diagnostic imaging with contrast agents. Curr Opin Chem Biol. 2002;6:642–50.

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Current Fluorescence-­Guided Platforms and Devices Donovan Hui, Kevin Carroll, Christina Sanders, and David Pechman

Introduction Fluorescence-guided surgery (FGS) enables clinicians to visualize fluorescence-enhanced images in real time to assist in surgical procedures. Its use has transformed the way surgeons visualize structures that may not be apparent under visible light alone [1]. The wavelength of visible light is between 380 and 780  nm. Near-­infrared (NIR) extends from a wavelength of 780–2500  nm with penetration of tissues ranging from 5 to

D. Hui Department of Surgery, New York Medical College Metropolitan Hospital Center, New York, NY, USA K. Carroll Department of Surgery, Northwell Health—South Shore University Hospital, Bay Shore, NY, USA C. Sanders Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA e-mail: [email protected] D. Pechman (*) Department of Surgery, Zucker School of Medicine at Hofstra, Northwell Health—South Shore University Hospital, Bay Shore, NY, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 N. Szoka et al. (eds.), The SAGES Manual of Fluorescence-Guided Surgery, https://doi.org/10.1007/978-3-031-40685-0_2

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8 mm [2, 3]. The depth of penetration and the working distance of each device determine which structures can be identified with fluorescence imaging. FGS utilizes a specialized camera with an NIR detector to relay images in real time. An excitation light source is used to activate fluorophores within target tissue [4, 5]. Excitation and emission wavelengths are specific for each device. These wavelengths are generally within a similar range and are limited by clinically available fluorophores [2, 3, 6, 7]. Fluorescence imaging requires a fluorophore or an NIR-­emitting LED to create near-infrared images. Fluorophores are compounds that release light with excitation and are the primary means for visualizing key structures in FGS. In 2021, available fluorophores include fluorescein, methylene blue (MB), 5-­aminolevulinic acid (5-ALA), and indocyanine green (ICG) [8]. ICG is the most frequently used fluorophore due to its ease of use and low side effect profile. It is easy to mix and administer intravenously in the pre-op or intraoperative setting. Its emission wavelength does not overlap with visible light; this minimizes scattering effect and background noise that may obscure visualization [8–10]. Fluorescein has an excitation wavelength of 495  nm and an emission wavelength of 519 nm. MB has an excitation wavelength of 668 nm and an emission wavelength of 688 nm. 5-ALA has an excitation wavelength of 380–440 and an emission wavelength of 620–634 nm, depending on the acidity of its solution. Fluorescein, MB, and 5-ALA have emission wavelengths within the visible light wavelength and are therefore not ideal fluorophores for FGS. The excitation and emission wavelengths of ICG are 740– 900 and 800–860 nm ranges, respectively, and are ideal for use with NIR cameras [11–13]. Fluoroscopic devices have become increasingly prevalent in the opening room since the Food and Drug Administration (FDA) approved the Novadaq SPY imaging system in 2005 [6, 12]. FGS has shown utility in a wide range of procedures, including intraoperative angiography, perfusion assessment, tissue plane identification, biliary structure identification, and lymphangiography [5, 14]. As the technology to fluorescently label specific tissues continues to advance, FGS devices will become increasingly more commonplace in the operative suite [8, 9].

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Indocyanine Green (ICG) Dye Indocyanine green (ICG) was developed in 1955 by Kodak Research Laboratory for NIR photography. It was approved for clinical use in 1959 for assessment of cardiac output. It was later found to be excreted exclusively by the liver with uptake by hepatocytes and excretion via bile which prompted its use in the assessment of hepatic function [15]. ICG was found to be useful in the assessment of choroidal blood flow and has since been utilized in an increasing number of angiographic and lymphangiographic modalities [11]. Use of ICG is heavily favored for fluorescenceguided surgery as it is a water-soluble dye with emission wavelength of approximately 800  nm. The autofluorescence at this wavelength in normal tissue is low which increases the signal-tonoise ratio and improves sensitivity of visualized target anatomy following excitation. ICG has a relatively low toxicity profile with a half-life at approximately 3 min. It readily binds lipoproteins in the blood without systemic effects and is very well tolerated by patients [16, 17]. It is non-nephrotoxic and has a low side effect profile. It can be used multiple times during the same surgery. ICG requires fresh preparation with 6 h of viable use. Contraindication for use of ICG is anaphylaxis. Recommended dosing, mode of administration, timing for administration, and timing for visualization are per manufacturer recommendations [17]. General recommendations are as follows: • Angiographic perfusion: 2.5  mg given intravenously during surgery with visualization in less than 1 min. • Biliary assessment: 5  mg given intravenously up to 1–7  h before surgery with direct visualization. • Lymph node mapping: 2.5 mg given directly around target tissue during surgery with visualization in 15–30 min.

Fluorescence-Guided Systems and Devices The first FDA-approved system for FGS is the Novadaq SPY system developed in 2005. Many of the first FGS systems were used in open surgery via a cart-based platform that contained

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an excitation laser and imager to capture NIR light. These cartbased systems have largely been replaced by handheld devices and have been adapted to laparoscopic, robotic, and microscopic systems. As FGS continues to advance, devices may integrate with augmented reality systems and wearable technology.

Open Surgical Systems The two categories of open FGS systems are cart-based and handheld devices. Cart-based systems offer visualization of key structures while freeing the surgeon’s hands to manipulate tissue and operate while assessing in real time. The working distance for such devices is fixed, but offers a wide area of visualization in assessing overall perfusion in reconstructive procedures. Handheld devices also offer visualization of key structures in real time with some systems having the option for mounting the imager on an adjustable securing arm. The size and convenience of handheld devices offer a greater degree of freedom and maneuverability with a flexible working distance [1, 3, 6].

Cart-Based Platform SPY Elite System [Spy Elite Intraoperative Perfusion Assessment System (LC3000, SP 3000)]—Stryker, Kalamazoo, Michigan, USA The SPY Elite System (Fig. 2.1a) is the updated version of the first clinically available FGS platform, the SPY System. The SPY Elite System consists of a mounted imaging head that can be positioned above the surgical field in order to obtain NIR images.

SPY Elite System Components The system includes the following: imaging console (radiation source and mage detector), dual display (1080p resolution),

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Fig. 2.1 (a) SPY Elite cart-based fluorescence system—Photo courtesy of Stryker. (b) SPY Elite fluorescence image—Photo courtesy of Stryker. (c) SPY-Q image captured for qualitative assessment of tissue perfusion—Photo courtesy of Stryker

CINEVAQ Software, sterile drape, and SPY AGENT GREEN (ICG)—25 mg vials. For use, the SPY Elite System should be positioned in the operating room to provide optimal visualization of the monitor located on the cart. The imaging console is sterilely draped, using the included clear drapes, and positioned over the surgical field. The imaging console is attached to a flexible arm mount connected directly to the cart system, which can be easily positioned and removed from the operative field while maintaining sterility. The working distance of the imaging console is 30 cm and is the ideal distance from the target anatomy to obtain accurate fluorescence images. SPY mode fluorescence is activated from the cart or the “laser on” button on the left side of the imaging console. The radiation source is a class 3R laser that activates a fluorophore to produce emission wavelengths between 825 and 850 nm. NIR images are captured through a charge-coupled device camera and relay real-time images on the display attached to the system cart. The preferred fluorophore with SPY Elite System is SPY AGENT GREEN (ICG), and its timing for use depends on the indication for use [18, 19].

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Dosing, Timing, and Route of Administration For angiography and assessment of tissue perfusion, ICG can be given immediately intraoperatively as an intravenous bolus injection of 1.25 to 5 mg. ICG can be injected directly into the skin for reconstructive surgeries in a dose of 3.75 to 10  mg. Maximum dose is 2 mg/kg. For visualization of extrahepatic biliary duct for use in patients ages 12 and older, ICG should be administered at least 45  min prior to surgery as an intravenous bolus injection of 2.5 mg. For lymphangiography, visualization of lymph nodes, and lymphatic mapping, ICG can be injected directly into target tissue as a direct injection of 5 mg or divided into four 1.25 mg injections around target tissue. As the first clinically available FGS system, the SPY System established the clinical utility of FGS but has largely been replaced by handheld devices and other newer systems. The FDA has determined the SPY Elite System was substantially equivalent to the predicate SPY System device as a fluorescence imaging system for use in imaging blood flow in plastic surgery (microscopic and reconstructive), gastrointestinal surgery, transplant surgery, cardiovascular surgery, and vascular surgery [20]. The SPY Elite System is able to provide real-time monochromatic images of fluorescent tagged structures (Fig. 2.1b) for the assessment of perfusion. SPY Elite contains updated processing and image acquisition software (CINEVAQ) that is able to overlay a color intensity gradient to the grayscale NIR image. This color intensity image can be recorded and reviewed to assess perfusion via SPY mode (Fig. 2.1c). SPY mode analyzes differences in near-infrared color intensities to offer objective values on estimated perfusion in the form of absolute perfusion units (APUs) to assess how well-perfused structures are during surgery [18–20]. The cart-based SPY Systems have been used across many surgical specialties since its clinical debut in 2005. Within the field of plastic surgery, it is used to assess tissue perfusion in reconstruction. SPY Elite laser angiography can help predict tissue necrosis following microvascular and reconstructive procedures such as

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facial reconstruction and nipple-sparing mastectomies [21–23]. Using the SPY proprietary software, absolute perfusion units (APUs) offer objective data on tissue perfusion with studies showing APUs of less than 24 associated with increased risk of tissue necrosis [24, 25]. A randomized double-blinded controlled study on complex abdominal wall reconstruction using the SPY Elite System displayed that real-time perfusion assessment could predict intraoperatively which patients were at increased risk for wound complications [26]. The SPY Elite System has been used for laser angiography of gastrointestinal anastomosis. SPY Elite angiography has displayed utility in assessing bowel perfusion when creating gastrointestinal anastomoses, but there have been no randomized controlled studies to assess whether its use decreases anastomotic failure [27–31]. The system has been used as an adjunct to assess graft patency following bypass in open heart surgery [32]. Recently, lymphangiography during sentinel lymph node biopsies has shown a non-inferior capability to identify lymph nodes compared to traditional approaches (radiofrequency labeling and application of dyes) [33, 34]. Pearls and Pitfalls • SPY mode relies heavily on the quality of near-infrared images. Tissue should be in plane with the imager at an ideal distance of 30 cm. • SPY perfusion assessment can be used in real time or saved for later review.

Handheld Devices SPY Portable Handheld Imaging (PHI): HH9000—Stryker, Kalamazoo, Michigan, USA SPY PHI (Fig.  2.2a) was initially developed by Novadaq Technologies as a handheld system approved for fluorescenceguided surgery in open surgical procedures. SPY PHI is the handheld version of the first clinically available fluorescence-guided

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Fig. 2.2 (a) SPY PHI handheld device—Photo courtesy of Stryker. (b) SPY PHI in SPY mode—Photo courtesy of Stryker. (c) SPY PHI in color-­ segmented mode—Photo courtesy of Stryker. (d) SPY PHI in overlay mode—Photo courtesy of Stryker

surgical system, the SPY System. The system consists of a handheld imager that is directly manipulated by the surgeon at target anatomy in order to obtain NIR images.

SPY PHI System Components The system includes the following: SPY PHI imager with integrated light cable, video processor/illuminator (VPI), display (1080p resolution), SPY PHI Fluorescence Assessment Software (SPY-QP), sterile drape, and SPY AGENT GREEN (ICG)— 25 mg vials. During use, SPY PHI platform is positioned for optimal visualization of the monitor. The handheld imager is connected to the video processor/illuminator with a light cable and camera cable. The imager is then sterilely draped, using the included clear drapes, and is now free to position sterilely in the operative field. The working distance of the imager is 10–40 cm. The green illumination button on the handheld device activates the light source and NIR laser for fluorescence excitation. The camera is able to detect full-color visible light and NIR images with the default

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image in overlay mode. The preferred fluorophore with SPY PHI System is SPY AGENT GREEN (ICG) with identical dosing and timing as with the SPY Elite System [35, 36]. Novadaq (now part of Stryker) developed its handheld fluorescence imaging system in 2017 with model HH9000. The currently available system is the SPY PHI model HH9000 now with SPY-­QP Fluorescence Assessment Software. The FDA has determined the current system was substantially equivalent to the predicate SPY Elite System for use in imaging blood flow in plastic surgery (microscopic and reconstructive), gastrointestinal surgery, transplant surgery, cardiovascular surgery, and vascular surgery. SPY PHI provides real-time visible and NIR imaging with multiple modes. SPY mode (Fig. 2.2b), color-segmented fluorescence (CSF) mode (Fig.  2.2c), and overlay mode (Fig.  2.2d) can be toggled using button “A” on the handheld device. SPY mode is a pure fluorescence image, displayed in monochromatic format to detect only NIR images. Color-segmented fluorescence (CSF) mode displays visible light in grayscale with fluorescence overlay in ­different color intensities to display fluorescence ranges (blue being the lowest to yellow and then red as the highest). Overlay mode allows for real-time visualization in the visible and NIR spectrum simultaneously, with fluorescence overlaid in green. SPY-QP software can be accessed from the handheld device via button “B” or through the VPI console. SPY-QP provides fluorescence assessment via relative percentage values (Fig. 2.2e) compared to a user set reference point and by color mapping similar to CSF mode [35–37]. Much like the SPY Elite System, the SPY PHI System has shown utility in a variety of clinical situations, including flap reconstruction, bowel anastomosis creation, and sentinel lymph node tracing [38, 39]. Because it is a handheld device, it has a more compact design that is user friendly in the operating room. Pearls and Pitfalls • Plug in device to the VPI prior to turning the system on to prevent “camera cable not detected” error. • Easy-to-use handheld controls to toggle fluorescence on and off (green button) and adjust focus of captured image (up and down blue buttons).

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• The VPI menu accessed from button “B” allows users to access SPY-QP and make adjustments such as flipping the image and capturing stills or video. Additionally, the reference point for SPY-QP assessment can be changed via this menu. • The device has a wide range working distance (10–40 cm). It is recommended that the user starts further away for better clarity in perfusion assessment. • SPY-QP should be activated prior to administration of ICG with recommendation to not change fluorescence mode during the timed perfusion assessment window (indicated by a red arrow and timer on the bottom right of the monitor). Photodynamic Eye (PDE)-neo II infrared fluorescence imager: C10935-400—Hamamatsu Photonics K.K, Higashi-ku, Hamamatsu City, Japan PDE-neo II (Fig. 2.3a) was developed by Hamamatsu Photonics as a handheld system approved for fluorescence-guided surgery in open surgical procedures. PDE-neo II is a handheld system designed to visualize ICG in the blood or lymph systems in real time. The system utilizes a handheld imager that can be directly held or mounted to a flexible arm to manipulate over the desired anatomy.

PDE-Neo II System Components The system includes the following: camera unit with attachable camera cable, controller box, remote controller, TEAC recording box, monitor, sterile drape, ICG dye, and PDE FlexArm. During use, the PDE-neo II platform is positioned for optimal visualization of the monitor located on the cart. The controller box is turned on and the camera unit is plugged directly into the input access on the far right. The TEAC recording box can be turned on to allow for video and image capturing but is not essential for use of the device. The camera unit is then sterilely draped and locked into the foam lens cover attached to the drape. An optional rail or clamp attachment for the flexible arm mount can

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Fig. 2.3 (a) PDE-neo-II handheld device—Photo courtesy of Hamamatsu. (b) PDE-neo-II in fluorescence mode—Photo courtesy of Hamamatsu. (c) PDE-neo-II in fluorescence mapping mode—Photo courtesy of Hamamatsu

be secured to allow for hands-free operation of the camera unit. The working distance of the camera unit is 5–30 cm and image clarity can be obtained using the adjustable focus ring. A non-­ sterile assistant can then turn on the white light and fluorescence mode using the remote controller. The handheld camera unit can then toggle between color and fluorescence at the discretion of the surgeon. Fluorescence excitation is achieved using a class 1M LED that produces infrared emissions at a wavelength of 820 nm. These infrared images can be captured via the camera unit with ambient room lights on but may scatter and produce poorer images if direct sunlight is present in the room. The timing and dose administration of a 2.5 mg/mL concentration of ICG varies depending on indications for use [29–37].

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Dosing, Timing, and Route of Administration For angiography and assessment of tissue perfusion, ICG can be given immediately intraoperatively as an intravenous bolus injection of 3.3 mL to 10 mL. For lymphangiography, visualization of lymph nodes, and lymphatic mapping, ICG can be injected into target tissue as a direct subcutaneous or intradermal injection of 0.5 mL around target tissue. PDE-neo II was originally developed by Hamamatsu Photonics with distribution within the United States via Mitaka USA Inc. Hamamatsu initially developed its handheld fluorescence imaging system in 2014 with the Hamamatsu PDE and subsequent PDE-­neo. The currently available system distributed by Mitaka since 2016 is the PDE-neo II. The FDA determined that the system was substantially equivalent to the predicate PDE-neo device for use in viewing fluorescence images of blood flow. PDE-neo II has two video channel outputs that can toggle between color mode and fluorescence mode (Fig.  2.3b). The fluorescence mapping mode (Fig.  2.3c) digitally enhances NIR images with green color which can define structures containing fluorescence compared to surrounding structures. The resulting image quality can be adjusted by using the brightness, contrast, and infrared intensity dials located on the remote controller [40–42]. PDE-neo II was designed as a fluorescent angiographic system for use in assessing tissue perfusion. It is commonly used in reconstructive surgery for flap assessment and has been found to assist clinical judgment when determining whether to resect additional tissue [43–45]. PDE-neo II can also assist in identifying resection margins in pulmonary and hepatic wedge resections [46]. PDE-neo II was able to successfully identify tumor margins during lung segmentectomy to maximize tissue preservation. PDE-neo II provides enhanced visualization of the thoracic duct during mediastinal lymphadenectomy to prevent chyle leak in thoracic surgery [47]. The device can also be utilized to evaluate patients with lymphedema for lymphaticovenous anastomosis and postoperatively to evaluate for anastomosis patency [48].

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Pearls and Pitfalls • Simple, lightweight handheld device with adjustable focus ring with surgeon control over infrared intensity and image toggling. • Remote controller separate from handheld device can adjust contrast and brightness to enhance visualization. • With initial use, recommend that the contrast, brightness, and infrared intensity dials are placed in their default locations marked on the remote controller.. • Visualization of halos during fluorescence mode may indicate infrared intensity is too high. Fluobeam LX—Fluoptics, Grenoble, France The Fluobeam LX (Fig. 2.4a) was developed by Fluoptics as a handheld system approved for FGS in open surgical procedures. Fluobeam LX is Fluoptics’ newest handheld system designed to visualize ICG fluorescence in blood vessels and tissue perfusion as well as autofluorescence from parathyroid tissue.

Fluobeam LX System Components The system includes the following: optical head with light cord, control box, touchscreen display, Fluosoft software, and sterile drape. For use, the Fluobeam LX is positioned with the touchscreen monitor in view of the surgeon. The controller box is turned on and the optical head with light cord is plugged directly into the input access on the far left. The optical head is sterilely draped with the optical window of the sterile drape attaching directly to the lens of the optical head. The fluorescence imaging system is now free to use with control of fluorescence imaging via the power button on the touchscreen display or accessed from the handheld joystick control. The system offers a high depth of field >5 cm with variable working distances with autofocus and up to 10× zoom. Fluorescence is achieved via class 1M laser which excites fluorophores with emissions in the range of 800–900 nm.

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Fig. 2.4 (a) Fluobeam LX system—Photo Courtesy of Fluoptics. (b) Fluosoft quantification analysis—Photo Courtesy of Fluoptics. (c) Fluobeam LX image of parathyroid autofluorescence—Photo Courtesy of Dr. Marco DeMarchi

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Infrared images can be captured via the camera unit with ambient room lights on. There are no device-specific recommendations for ICG dosing or timing with use of this device. Autofluorescence from parathyroid tissue does not require ICG [49, 50]. Fluoptics developed its handheld fluorescence imaging system in 2014 with the Fluobeam 800 Clinic Imaging Device. Although the Fluobeam 800 remains clinically available, the Fluobeam LX is the most recent system created by Fluoptics with emphasis on parathyroid surgery. The FDA has determined the current system is substantially equivalent to the predicate Fluobeam device as a fluorescence imaging system for use as an adjunctive method to evaluate tissue and organ perfusion used in plastic surgery (microscopic and reconstructive) and transplant surgery [51–53]. Additionally, it has been FDA approved to observe autofluorescence of parathyroid glands without the injection of ICG. Fluobeam provides real-time NIR imaging with fluorescence mode with Fluosoft optimization of images. Fluosoft available on Fluobeam 800 provides quantification analysis that overlays color representation of relative tissue perfusion (Fig. 2.4b). The relative tissue perfusion shows maximal reference perfusion in red and lower relative perfusion in black/blue. Perfusion assessment has been shown to be effective even with angulation of the optical head from 60 to 90° to the tissue (#). Image quality is automatically optimized by Fluosoft software and contrast of images can be adjusted by the surgeon via joystick controls [50]. Fluobeam LX was designed as a fluorescence system for use as an adjunctive visual assessment in parathyroid surgery. Fluobeam is commonly used in endocrine surgery during parathyroid and thyroid surgery with its ability to detect parathyroid autofluorescence without the use of ICG [50, 54]. Fluobeam LX has been successful in the fluorescence visualization of parathyroid adenomas (Fig. 2.4c) for resection and parathyroid tissue for preservation during thyroidectomy [55, 56]. With ICG, Fluobeam LX is able to intraoperatively identify lymphatics and sentinel lymph nodes for biopsies and is equivalent in accuracy to radioactive tracing [53]. Perfusion assessment using Fluobeam with associated Fluosoft quantification analysis during reconstructive s­ urgery has shown that relative perfusion of less than 30% to likely be nonviable tissue [52].

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Pearls and Pitfalls • If autofocus produces distorted images, adjust the zoom to decrease magnification for clearer images. • Touchscreen display has many options to adjust image for fine-­ tuned assessment of captured image which can all be toggled using the handheld joystick on optical head. • Images and video can be easily accessed using playback mode. • ICG is not needed with autofluorescence of parathyroid tissue, but may still be used to additionally visualize blood vessels to aid in tissue dissection.

Endoscopic Surgical Devices Fluorescence in minimally invasive procedures has been used in clinical settings since 2009. FGS has become more prevalent in minimally invasive surgery. The first endoscopic system was the PINPOINT System developed by Novadaq. Its use as the first endoscopic FGS device has been well-documented. The PILLAR (perfusion assessment in left-sided/low anterior resection) trial displayed that the PINPOINT System allowed for successful visualization of perfusion using ICG; however, it did not display a significant difference in anastomotic leak rate with use of ICG angiography [57]. Indications for all minimally invasive FGS devices include the identification of vessels, extrahepatic bile ducts, and lymphatics and assessment of tissue perfusion [57, 58]. PINPOINT Endoscopic Fluorescence Imaging System: PC9000—Stryker, Kalamazoo, Michigan, USA PINPOINT System (Fig.  2.5a) was initially developed by Novadaq Technologies as an endoscopic fluorescence system for use in minimally invasive surgical procedures. PINPOINT was the first clinically available endoscopic fluorescence-guided surgical system. The system consists of a handheld camera head that attaches to a laparoscope for capturing visible light and near-­ infrared light images obtained in minimally invasive surgical ­procedures.

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Fig. 2.5 (a) PINPOINT: laparoscope—Photo courtesy of Stryker. (b) PINPOINT SPY mode—Photo courtesy of Stryker. (c) PINPOINT color-segmented mode—Photo courtesy of Stryker. (d) PINPOINT overlay mode—Photo courtesy of Stryker

PINPOINT System Components The system includes the following: video process/illuminator (VPI), PC9001; camera head with light guide cable, PC9002/ PC9004; camera (resolution 1080p); fluorescence imaging laparoscopes, SC9000 series (5  mm, 10  mm), 0 and 30° scopes; PINPOINT Cart with 1080p HD monitor and optional recorder and printer; and SPY AGENT GREEN (ICG)—25 mg vials. To use, PINPOINT is set up similar to any other laparoscopic surgical system with placement of monitors depending on surgical indications. The camera head with light guide cable and laparoscopes are autoclavable and will be handed to the surgeon sterilely. The laparoscope eyepiece is attached to the camera head and the light cable attached to the laparoscope via threaded connector. The light cable and camera cable are then handed off to a non-­sterile assistant to plug into the VPI with light cable inserted into the far left, orange-colored input, and the camera cable inserted into the far right, green-colored input. After the cable

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inputs have been plugged in, the VPI can be turned on for use as a laparoscopic camera with only white light on. The working distance is not specified for this device, but it is recommended to image in PINPOINT mode further away from target anatomy prior to advancing the laparoscope. PINPOINT mode is activated by pressing button “1,” and the laser-on indicator located on the camera head will illuminate as well as a PINPOINT icon on the main display. PINPOINT contains a dedicated light source with a light-­emitting diode (LED) array for visible light and an NIR laser diode for near-infrared. Fluorescence excitation is achieved using a class 3R laser which produces excitation wavelength at 805 nm and near-infrared emissions from 700 to 770 nm. The preferred fluorophore with PINPOINT System is SPY AGENT GREEN (ICG), and its use in angiography should be given intraoperatively as a weight-dependent bolus delivered intravenously. Maximum dose is 2  mg/kg body weight. Fluorescence will appear within blood vessels in the field of view within 5–15 seconds after the injection [21, 59, 60].

Dosing, Timing, and Route of Administration For patients less than or equal to 90 kg, use 0.5 ml of a 2.5 mg/ml concentration. For patients greater than 90 kg, use 1–1.5 ml of a 2.5 mg/ml concentration. Novadaq (now a part of Stryker) developed its endoscopic fluorescence-­guided systems in 2009 with the SPY Scope: SC8000. The currently available system is the PINPOINT System: PCS:9000. The FDA has determined the current system is substantially equivalent to the predicate PINPOINT System and SPY Scope as an endoscopic fluorescence imaging system for use in endoscopic assessment of vessels, blood flow, and tissue perfusion as well as fluorescence imaging of biliary ducts. PINPOINT provides real-time visible and NIR imaging with an operating principle of SPY mode (Fig. 2.5b), color-segmented fluorescence (CSF) mode (Fig.  2.5c), and overlay mode (Fig.  2.5d), which can be toggled using button “2” on the camera head. SPY mode is a pure fluorescence image, displayed in monochromatic format to detect

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only NIR images. Color-segmented fluorescence (CSF) mode displays visible light in grayscale with fluorescence overlay in different color intensities to display fluorescence ranges (blue being the lowest to yellow and then red as the highest). Overlay mode allows for real-time visualization in the visible and NIR spectrum at the same time with fluorescence overlaid in green. Parallel display will show all operating principles on one display [59, 60]. PINPOINT System is widely known as the progenitor fluorescence-­guided surgical system that allows for fluorescence visualization as a laparoscope. It was intended for use in minimally invasive surgical cases and was designed as an adjunctive visual assessment in tissue perfusion and biliary ducts with fluorescence labeling. It is not intended as a standalone visualization of the biliary ducts in lieu of cholangiography. Most recently, it has been approved for use in lymphatic visualization with ability to fluorescence image lymph nodes and lymphatic vessels such as during lymphatic mapping of the uterus and cervix [61]. Pearls and Pitfalls • Parallel display can show singular overlay images or multiple images that display both white light and NIR light images together without overlay. • Damage to the laparoscope tip or light cable tip can affect apertures for NIR emission causing a scattering effect. • If the entire image shows strong fluorescence signal throughout, the laparoscope may be an HD laparoscope instead of a fluorescence laparoscope. • Image quality settings (sharpness, brightness, color saturation) can be adjusted via the display monitors, but adjustment of the focus is via the up and down arrows located on the camera head. Synergy ID Near-Infrared Fluorescence 4K Imaging Platform—Arthrex, Munich, Germany SynergyID (Fig. 2.6a) was developed by Arthrex to complement its endoscopic system with the capabilities of fluorescence-­guided surgery in minimally invasive procedures. The basis for Arthrex

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Fig. 2.6 (a) SynergyID System—Photo courtesy of Arthrex. (b) SynergyID System—Photo courtesy of Arthrex. (c) SynergyID System—Photo courtesy of Arthrex. (d) SynergyID System—Photo courtesy of Arthrex. (e) SynergyID System—Photo courtesy of Arthrex

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Fig. 2.6 (continued)

fluorescence-guided surgical device is the high-quality imaging using UHD4 camera system. The current SynergyID System consists of a camera head with 4 chip image processing to provide high-definition standard light and near-infrared light images.

 ynergyID Endoscopic Imaging System Platform S Components The system includes the following: imaging console/camera control unit, AR-3200-0025; camera head option for fluorescence, 4K SynergyID; synergy laser light source and light cable, AR-3200-­1018; laparoscope, AR-3351 (5  mm high magnification, 10  mm) with 0, 30, and 45° scopes; and tablet controller (Digital Doc Tablet). The tower for the Synergy ID contains the imaging console/ camera control unit and the synergy laser light source. The unit is initially turned on via the green switch in the back of the power unit. The tablet controller can then connect to the console and users can select cases and patient lists for optimizing image settings. The tablet controller offers a unique way for surgeons to set up preferences and review cases for planned surgical interven-

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tions. Once the patient is prepped and ready for a procedure, the autoclavable camera head, light cables, and laparoscopes can be connected to one another and input cables connected to the tower. The camera cable is plugged into the input on the far right, while the light cable, which has a split output (one for the imaging console for standard light and one for the laser light source), can be connected accordingly. Fluorescence mode for the SynergyID can be activated from either the tablet or the programmable buttons located on the camera head. The SynergyID laser light source contains a class 3R laser with 8 mm of penetration and generates infrared emission wavelength at 785  nm. There are no device-­ specific recommendations for timing or dosing of ICG. Arthrex developed the SynergyID device in 2020. The FDA determined that the system was substantially equivalent to the predicate Arthrex UHD4 System and Novadaq’s PINPOINT for use as a camera system in all endoscopic procedures and a fluorescence-­guided surgical system for the visual assessment of vessels, blood flow, extrahepatic bile ducts, and tissue perfusion. The SynergyID System offers 4K standard light images and NIR images. The default operating principle while in fluorescence mode is overlay mode (Fig.  2.6b). The different fluorescence images can be cycled by pressing the programmed buttons on the camera head with grayscale visible and NIR overlay (Fig. 2.6c) or NIR-only (Fig. 2.6d) imaging [62–64]. The color of fluorescence can be changed from green to other colors, such as red, cyan, and magenta. The SynergyID System can further enhance the high-­ definition images via its augmented reality features [65]. This allows users to filter red colors that can enhance visualization (Fig. 2.6e) as an additional customizable view for the surgeon [65, 66]. The Arthrex SynergyID system is intended to be used as an endoscopic video camera for a variety of surgical procedures. These can range from orthopedic, laparoscopic, urologic, sinuscopic, and plastic surgical procedures including microscopic surgery. The laser light source allows SynergyID to visualize NIR images for use in general FGS procedures such as in the visualization of blood vessels, extrahepatic bile ducts, and lymphatics with 4K high-resolution imaging [62, 66].

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Pearls and Pitfalls • UHD4 camera system with 4K high-resolution images offers greater depth perception and color clarity. • The rotatable turret for the light guide has a number of light inputs compatible with different cables. Ensure the correct port is aligned with the LED prior to inserting light cable. • Camera has programmable buttons to allow surgeon to easily toggle desired display settings. • Digital Doc Table can be used to store and configure case preferences remotely. Visera Elite II Infrared Imaging System—Olympus, Fukushima, Japan The Visera Elite II Infrared Imaging System (Fig.  2.7) was developed by Olympus as an endoscopic system for fluorescence-­ guided minimally invasive surgery. The Visera Elite II Infrared Imaging System attaches to a xenon arc lamp excitation source. This light source allows for infrared (IR) illumination that is visualized via specialized IR endoscopes.

Fig. 2.7  Visera Elite II Infrared System—Photo courtesy of Olympus

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Visera Elite II Components The system includes the following: Visera Elite II Video System Center; infrared imaging system; xenon light source; autoclavable camera head, CH-S200-XZ-EB; and the telescope IR/ultra (specialized IR endoscope). The device consists of the source circuit, control circuit, illumination lamp, and optical filter. The control circuit is connected to the diaphragm to control light intensity with the source circuit supplying power to the illumination lamp. After the control unit is activated, the IR endoscope is connected. The IR endoscopes are rigid and consist of an image relay system of rod lenses that transmit either a 2D or 3D image for standard laparoscopy. The IR endoscopes are reusable and fully autoclavable. There are no device-specific recommendations for dosing or timing of ICG injection [67, 68]. Olympus developed the Visera Elite II Xenon Light Source Olympus (CLV-S200-IR) in 2020. Olympus initially developed an FGS device after the acquisition of Quest Photonic Devices. Quest innovations, based in the Netherlands, was established in 1998 and specialized in fluorescence and multispectral technologies to offer enhanced visualization of tumor margins during oncological surgery. This was the foundation for the eventual production of the Visera Elite II product line. The FDA determined that the system was substantially equivalent to the Karl Storz Endoscopic ICG imaging system [67]. The Visera Elite II utilizes a control circuit with an optical filter to provide a clear image. The fluorescent light passes through the optical filter in the endoscope, allowing the surgeon to work in one of two IR modes: IR mode 1 and IR mode 2. IR mode 1 displays fluorescent illumination overlaid on a clear white light image the visualization of detailed structures. IR mode 2 displays the pure fluorescence image with the highest degree of contrast on a black and white image [67, 68]. The Visera Elite II Infrared Imaging System is intended to provide real-time endoscopic visible and near-infrared fluorescence imaging. These endoscopes are intended to be used for endoscopy and endoscopic surgery within the thoracic and peritoneal cavities including the female reproductive organs. The device is also

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i­ndicated for visualization of transanal and transvaginal natural orifice surgery. The system is approved for use in the assessment of vessels, tissue perfusion, and biliary anatomy [67]. Pearls and Pitfalls • The system includes a compact video system center in one modular device that is compatible with 3D laparoscopes. • A 3D image rotation function maintains the horizon as 30° scopes are rotated. • The lightweight camera head can control and toggle between desired infrared imaging modes.

Open/Endoscopic Devices A number of recently updated systems have been able to integrate open and endoscopic systems with fluorescence capabilities into one platform. These systems are able to integrate interchangeable cameras or scopes to enable use for both open and minimally invasive surgical procedures. 1688 Advanced Imaging Modalities (AIM) 4K Platform— Stryker, Kalamazoo, Michigan, USA 1688 AIM 4K Platform (Fig. 2.8a) was initially developed by Stryker as a platform capable of endoscopic fluorescence imaging for use in minimally invasive surgical procedures as well as handheld fluorescence imaging in open surgical procedures using SPY PHI. 1688 AIM is the endoscopic portion of the platform. The endoscopic system consists of a handheld camera head that attaches to a laparoscope for capturing visible light and NIR light images obtained in minimally invasive surgical procedures.

1688 4K Platform Components The system includes the following: 1688 4K camera control unit with advanced imaging modalities 1688 4K resolution camera head options, camera head with AIM; microscope head, pendu-

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lum head, or inline head; L11 LED light source and safelight cable; AIM HD laparoscope; display (4K resolution); connected OR hub (optional for recording and customizing visualization settings); SPY PHI System for handheld/open procedures; and SPY AGENT GREEN (ICG)—25 mg vials. a

Fig. 2.8 (a) AIM 1688 with SPY PHI System—Photo courtesy of Stryker. (b) AIM 1688 overlay mode—Photo courtesy of Stryker. (c) AIM 1688 contrast mode—Photo courtesy of Stryker. (d) AIM 1688 ENV mode—Photo courtesy of Stryker

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For use, 1688 AIM’s connected operating room cart is set up similar to any other laparoscopic surgical system with placement of monitors depending on surgical indications. The camera head with light guide cable and laparoscopes are autoclavable and will be handed to the surgeon sterilely. Depending on the type of ­camera head, a coupler may need to be installed to connect the camera head to the laparoscope eyepiece. The laparoscope eyepiece is attached to the coupler on the camera head and the light cable attached to the laparoscope via the threaded connector. The light cable and camera cable are then handed off to a non-sterile assistant. The camera cable connector is protected by a soaking cap which is removed, and the connector is plugged into the input on the camera control unit. The safelight cable is plugged into the L11 LED light source. From the camera control unit, the type of surgery can be selected from an option of nine different surgical specialties which individually optimize the camera settings based on the desired surgical procedure. The specialty selected on the camera control unit should be “laparoscopy” or “standard”; otherwise, fluorescence mode will not activate. After the cable inputs have been plugged in, the camera can be white balanced and “auto” light setting can be turned on if desired. Auto light will automatically adjust the brightness as needed throughout the case. SPY mode is the fluorescence mode of the 1688 AIM and is controlled by pressing “AIM” on the camera control unit. Additionally, SPY mode can be activated by the surgeon by pressing the menu button on the right of the camera head. The L11 LED light source for the 1688 AIM System utilizes both RGB (red, green, blue) LEDs and a class 1M laser for excitation with wavelength of 806  nm for NIR fluorescence. The preferred fluorophore with AIM 1688 is SPY AGENT GREEN (ICG) with similar timing and dosing as with SPY Elite [69, 70].

Dosing, Timing, and Route of Administration For angiography for visualization of blood vessels and tissue perfusion, ICG can be given immediately intraoperatively. For patients less than or equal to 90  kg, use 0.5  ml of a 2.5  mg/ml

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concentration. For patients greater than 90 kg, use 1–1.5 ml of a 2.5 mg/ml concentration. Maximum dose is 2 mg/kg. For visualization of extrahepatic biliary duct for use in patients ages 12 and older, ICG should be given at least 45 min prior to surgery as an intravenous bolus injection of 1 ml of a 2.5 mg/ml concentration. For lymphangiography, visualization of lymph nodes, and lymphatic mapping, ICG can be injected directly into target tissue as multiple direct injections of 0.5 ml of a 2.5 mg/ml concentration as needed. 1688 AIM 4K Platform was developed by Stryker and is the endoscopic portion of the system that includes the SPY PHI handheld device. Stryker developed an endoscopic fluorescence device in 2014 with the Stryker Infrared Fluorescence (IRF) Imaging System. The currently available system is the 1688 AIM 4K camera system with L11 LED light source. The FDA determined that the system was substantially equivalent to the predicate devices 1588 AIM and Stryker IRF for use as a camera system in all endoscopic procedures and as an FGS system approved for the visual assessment of vessels, blood flow and tissue perfusion, biliary ducts, and lymphatic vessels and nodes. The L11 LED light source is also intended to attach to Stryker’s IRIS Ureteral Kit to transilluminate the ureters producing NIR emissions at 830 nm for open and laparoscopic cases. 1688 AIM provides real-time visible and NIR imaging with fluorescence activated in SPY mode. The operating principle for SPY mode is overlay mode (Fig. 2.8b), contrast mode (Fig. 2.8c), and ENV mode (Fig. 2.8d). The different SPY modes can be changed by pressing the up button on the camera head. Overlay mode allows for real-time visualization in the visible and NIR spectrum simultaneously with fluorescence overlaid in green. Contrast mode is a pure fluorescence image, displayed in monochromatic format to detect only NIR images as white color. ENV mode displays visible light in grayscale with fluorescence overlay in green [68–70]. The 1688 AIM camera system can be used with and without fluorescence. There are nine surgical specialties that can be supported by this system and are selectable from the camera control unit for specific image optimization. The nine specialties for use with the camera system are general laparoscopy, ENT/skull

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endoscopy, arthroscopy, cystoscopy, flexi-scope, hysteroscopy, laser, microscope, and standard use. The fluorescence functionality is only available for laparoscopy and standard and intended for use in minimally invasive surgical cases as an adjunctive visual assessment in tissue perfusion, biliary ducts, and lymphatic ­mapping. Open surgical cases can use the SPY PHI attached to the platform. The L11 LED light source can connect to IRIS ureteral stents for transillumination of the ureters in open and laparoscopic cases. This has proven beneficial in difficult pelvic dissections to visualize the ureters and prevent injury [71]. Pearls and Pitfalls • The platform has an independent handheld fluorescence-­ guided system, SPY PHI, which can be used in conjunction with 1688 AIM. • The system displays images in 4K resolution. • The display can show singular overlay images or multiple images in parallel that display both white light and NIR light images together without overlay. • Specialty select on the camera control unit should be set to “laparoscopy” or “standard” in order for fluorescence SPY mode to activate. • L11 LED light source needs to be connected to the camera control unit for auto light to work. • If image quality remains poor, the coupler may not be attached correctly to the camera head and laparoscope eyepiece. Image 1S Rubina—Karl Storz, Tuttlingen, Germany The Image 1S Rubina (Fig. 2.9) was developed by Karl Storz as a fluorescence capable, modular system for use in minimally invasive and open surgical procedures. Rubina builds on the Image 1S Camera System and can incorporate 4K, 3D, NIR/ICG, and LED components as needed. The fluorescence-guided surgical system consists of a Rubina camera head that attaches to a laparoscope or exoscope for capturing visible and NIR images in minimally invasive and open surgical procedures, respectively.

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Fig. 2.9  Image 1s Rubina System—Photo courtesy of Karl Storz

Rubina: ICG Imaging System Components The system includes the following: Rubina LED light source; camera control unit, TC201US; TC 304US; light cable; camera head options, OPAL 1 (NIR/ICG); IMAGE 1S Rubina (4K, NIR/ ICG); TIPCAM 1 Rubina (4K/3D, NIR/ICG); laparoscope, Hopkins ICG/NIR (5  mm, 10  mm); exoscope, VITOM II ICG; footswitch; monitors with 4K or 4K/3D resolution; and 3D clip on glasses. For use, the Image 1S Rubina’s operating room cart is set up similarly to any other laparoscopic surgical system, with monitors placed for optimal visualization. 4K and 4K/3D displays can be used. The camera head with light cable and scopes are autoclavable and will be handed to the surgeon sterilely. There are multiple camera head options that provide NIR/ICG images. The camera head, scope, and light cables are attached to one another, and the camera and light cables are then handed off to a non-­ sterile assistant. The camera cable inserts into the camera control unit and the light cable inserts into the Rubina LED light source. For open surgical procedures, the exoscope and camera head can

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be attached to a flexible arm mount as needed. Fluorescence is activated by the lower button on the camera head or via a connectable footswitch. The system utilizes a laser-free excitation source of an LED and has infrared emission wavelength at 720–810 nm. There are no device-specific recommendations for timing or dosing of ICG injection with this system. Image 1S Rubina System was developed by Karl Storz as a fluorescence capable system for minimally invasive and open surgeries. Karl Storz developed an ICG imaging system in 2016 with the OPAL ICG/NIR systems. The FDA has determined that the Image 1S Rubina is substantially equivalent to predicate device for use as a camera system in all endoscopic procedures and as an FGS system approved for assessment of vessels, tissue perfusion, biliary ducts, and lymphatic vessels and nodes. Rubina is compatible with a variety of camera head options to allow for standard imaging, NIR imaging, and imaging in 4K or 4K/3D. The camera system can be fitted for both endoscopes in laparoscopic cases and an exoscope with flexible arm mount for open cases. For NIR images, the system can accommodate an overlay of white light and NIR images on a single display with either green or blue NIR-­ enhanced images. Intensity map displays the intensity of signals in an overlay image while removing white light images to maximize visualization of fluorescently labeled structures. Monochromatic NIR imaging can overlay NIR images and black and white visible light images for visual contrast [72–74]. The compatibility of the system with multiple camera heads and scopes allows for high-definition and 3D-compatible imaging which can be used for laparoscopic and arthroscopic procedures. The Image 1S Rubina can be used with and without fluorescence imaging. Indications for use with fluorescence include assessment of blood vessels, tissue perfusion, visualization of the biliary system, and lymphatic tracing [75, 76]. Pearls for Use • Image 1S camera compatible with both laparoscope and exoscope for minimally invasive and open surgery. • System includes a foot pedal for toggling fluoroscopic imaging.

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• System is compatible with 4K and 4K/3D imaging. • System can display NIR images in two colors (blue and green). • User can modulate intensity of NIR images to optimize visualization. EleVision IR Platform—Medtronic, Dublin, Ireland EleVision (Fig. 2.10) was developed by Medtronic as a fluorescence capable surgical system for use in minimally invasive and open surgical procedures. The system is able to be used in both minimally invasive and open surgery by having a camera capable of attaching to either a laparoscope or a microscope.

EleVision IR Platform Components The system includes the following: fluorescence camera, Visionsense 3 Iridium (VS3-IR); Iridium Module Scope, Visionsense 3 Miniature Microscope (VS3-MMS); camera control unit; laser light source (LLS); xenon light source; touchscreen monitor; VS3 Iridium Endoscopes (5  mm, 10  mm); VS3 Light Cable and Iridium Light Beam Combiner; sterile drapes for VS3MMS; VS3-IR Fluorescence ICG Kit; and Iridium software. The EleVision IR Platform tower’s main components for fluorescence imaging are the camera control unit and laser light source. For minimally invasive surgery, the camera head, scopes, and light cable are autoclavable and are handed to the surgeon sterilely. The camera is assembled and the camera cable and light cable are handed to a non-sterile assistant. The camera cable has a protective cap which is removed prior to insertion into the camera control unit with its input located on the left side of the unit. The light cables are attached to the laser light source and the xenon light source (which is the standard light for use in general laparoscopy). For open surgery, the VS3-IR camera is attached to a non-­ autoclavable iridium module scope: VS3-MMS which can be handheld or attached to a cart-mounted arm for positioning over a surgical field with a working distance of 17–50  cm. It must be sterilely draped prior to use during operative procedures with fixation of the drape window to the scope. Fluorescence can be activated and controlled from the handheld camera head. The

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Fig. 2.10  EleVision IR System—Photo courtesy of Medtronic

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device utilizes a laser excitation light source and has infrared emission wavelengths at 785–805 nm with penetration 3–5 mm of tissue. There are no specific timing or dose recommendations for injection of the ICG [77, 78]. EleVision IR Platform was developed by Medtronic as a fluorescence capable system for minimally invasive and open/microscopic surgeries. Visionsense, now a part of Medtronic, had developed its endoscopic and handheld fluorescence device in 2014 with the VS3-IR and VS3-MMS, respectively. This system has since been integrated into Medtronic’s EleVision IR Platform as of 2018, and the FDA determined that the system was substantially equivalent to predicate devices for use as a camera system in FGS, approved for the visual assessment of vessels, tissue perfusion, biliary ducts, and lymphatic vessels and nodes. Both cameras utilize a dual-channel camera system for imaging of both standard visible light and NIR light images at high resolution up to 4K. Fluorescence images are displayed in monochromatic NIR imaging, in false color NIR imaging, and in overlay mode. False color NIR assigns different colors based on NIR intensity (blue being the lowest to yellow and then red as the highest). Infrared intensity can also be assessed by the Iridium software which offers quantitative and qualitative measurements of infrared signal intensity based on absolute and relative pixelations of images. This software can offer real-time relative quantitative values regarding tissue perfusion with heat mapping [77–79]. The compatibility of the VS3-IR camera with a laparoscope or miniature microscope allows the system to be used in laparoscopic and open cases. EleVision IR Platform can be used with and without fluorescence imaging. Indications for use of fluorescence using the EleVision IR are for the assessment of vessels, tissue perfusion, visualization of the biliary system, and lymphatic tracing. Pearls for Use • Available as either open, minimally invasive, or combined system. • Capable of 4K high-resolution images.

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• Iridium software can analyze images in real time to provide both quantitative and qualitative information on perfusion. • Display can show singular overlay images or multiple images that display both white light and NIR light images together without overlay. • Two separate channels for the camera each require focus adjustment as needed. Quest Spectrum—Olympus Surgical Technologies, Hamburg, Germany Quest Spectrum (Fig. 2.11) was developed by Quest Photonic as a fluorescence capable surgical system for use in minimally invasive and open surgical procedures. The system consists of a camera head, which can attach to one of two different scope

Fig. 2.11  Quest Spectrum System—Photo courtesy of Quest and Olympus

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components. These components are easily interchangeable and can be exchanged during a procedure.

Quest Spectrum Components The system includes the following: Quest Spectrum camera with video cable, ring light with light cable, laparoscope with light cable, display monitor and control tower, light engine, and sterile drapes. Quest Spectrum utilizes a common camera head for minimally invasive and open surgical procedures. For minimally invasive surgery, the camera head and laparoscope base are sterilely draped to allow for attachment of the laparoscope and light cable. The camera cable will have already been connected to the system and the light cable can be inserted into the light engine on the far right. For open surgery, the ring light and light cable are attached to the camera and are sterilely draped with fixation of the connecting lens to the ring light. The device can then be used as a handheld device or attached to a flexible arm mount over a surgical field with a working distance of 5–30  cm. Fluorescence can be activated from the camera control or cart console. The camera contains two NIR channels and thus ultimately captures three different images: white light image and two different NIR images. The light engine produces the LED light for visible light images, while the modular laser light source produces laser for excitation with capturable infrared emission wavelengths at 700–830  mm and 830–1100 nm. There are no device-specific recommendations for timing or dosing of ICG injection [80, 81]. Quest Spectrum was originally developed by Quest Photonic Devices (now part of Olympus Corporation) as an open and endoscopic system in 2015. At that time, it was initially known as the Artemis Handheld System and was compatible with a ring light for open surgery and laparoscopes for minimally invasive surgery. The FDA determined that the Quest Spectrum system is substantially equivalent to the predicate Artemis system for use as a camera system in FGS, approved for assessment of vessels, tissue perfusion, biliary ducts, and lymphatic vessels and nodes. The system monitor can display visible light, monochromic fluores-

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cence, and overlay of colored fluorescence on visible light images. Since the system has two NIR channels, the overlay mode can display two different NIR emission wavelengths in two different colors to identify multiple fluorescent tagged structures [79]. The Quest Spectrum can be used in both laparoscopic and open cases and can be used with and without fluorescence imaging. Indications for use of fluorescence are for the assessment of vessels, tissue perfusion, visualization of the biliary system, and lymphatic tracing [81, 82]. Pearls and Pitfalls • System includes a single camera with interchangeable attachments for use in either open or minimally invasive surgery. • Both open and laparoscopic uses of the system will require sterile drapes to cover the camera head. • The system includes two channels for two NIR images with ability to toggle between wavelengths in green and blue image enhancement. • The display can show singular overlay images or multiple images that display both white light and near-infrared light images together without overlay.

Robotic Surgical Systems Firefly—Intuitive Surgical, California, USA Firefly (Fig. 2.12a) was developed by Intuitive Surgical to add fluorescence-guided capabilities to its minimally invasive robotic surgical platform. Firefly is a standard integrated feature with Da Vinci Robotic Systems and does not require additional modules or attachments to utilize.

Firefly Components The system includes the following: 8 mm 0° and 30° endoscopes (PNs 470,026 and 470,027), endoscope controller (PN 372601),

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Fig. 2.12 (a) Da Vinci Xi Endoscope Plus with fluorescence capability— Image courtesy of Intuitive. (b) Firefly mode—Image courtesy of Intuitive. (c) Firefly sensitive mode—Image courtesy of Intuitive

fluorescence imaging kit (K101077) (PN 950156), and Da Vinci Xi Robotic Components.

Instructions for Use The Da Vinci Xi Robotic System is set up in its usual sterile fashion. Once the robot is docked, the surgeon has full access to the Firefly system. The console allows easy switching between normal illumination and fluorescence imaging modes. The camera head optics are optimized to visualize a fluorescence signal. The surgeon will then have full control over near fluorescence imaging. The camera unit is a 3D stereoscopic scope and cable that contains an LED light source, excitation light, and camera. The

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Firefly system utilizes an excitation source of a class 3R laser and has infrared emission wavelength at 805  nm. The working distance is 2–14  cm. The visualization of near-infrared frequency can easily be toggled from the operative console and offers LED illuminated black and white visualization with green color-­ enhanced fluorescence (Fig. 2.12b). Additionally, sensitive mode (Fig. 2.12c) will toggle off the visible light LED to better enhance visualization of deeper near-infrared structures up to 8–10 mm in depth. In sensitive mode, the system automatically adjusts signal intensity and brightness to allow for a consistent image regardless of the distance between the endoscope and tissue. The imaging LED illuminator emits a laser to excite ICG.

Dosing, Timing, and Route of Administration The recommended dosing for ICG is 0.5–1.5 ml at 2.5 mg/ml concentration with the maximum daily dose not to exceed 2 mg/kg body weight. ICG has a half-life of 2–5 min. It should be used within 6 h of reconstitution. ICG stays within blood vessels for seconds and one should see fluorescence dye within 5–50 seconds. ICG stays within the kidney for 20 min with visibility within 1 min, the liver for 1–2 h with visibility within less than 2 min, and bile for 1–2 h with visibility within tens of min [83–86]. This timing of onset of visibility and the time it lasts can be used by the operating surgeon as to when to administer the ICG based on the operative case and target tissue to be visualized. Intuitive developed a robotic fluorescence device in 2011 with the Da Vinci Si platform. Intuitive collaborated with Novadaq to incorporate fluorescence imaging into its robotic surgery platform. The current system available is Firefly and is a component of the Intuitive Da Vinci Xi platform. This system includes a 1080i 3D stereoscopic fluorescence camera with LED illuminator and laser generator. The indications for Firefly include the assessment of vessels and tissue perfusion and the evaluation of the extrahepatic biliary system [87, 88].

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Pearls and Pitfalls • Firefly is easy to control from the surgical console. • Firefly can be activated using the finger clutch at the robotic console, so visualization can be maintained as fluorescence is turned on and off. • A surgeon can activate sensitive mode for greater visualization of NIR images and for visualization of deeper structures. • Overlay mode not currently available. ActivSight™—Activ Surgical, Boston, MA, USA ActivSight™ is an FDA-approved modular imaging device that integrates with the standard laparoscopic vision system to provide multimodal visual intelligence beyond the human visual spectrum. ActivSight™ has three components: the imaging module (IM), the light engine (LE), and the bifurcated light guide (LG). The IM is placed between the laparoscope and standard white light camera. The IM contains a sensor that captures light within the infrared spectrum while passing light in the visual spectrum to the white light camera. The LE illuminates the surgical field with white light and wavelengths of light in near-infrared (NIR) spectrum. The images obtained from the white light and infrared cameras are combined to create overlay images that display real-time tissue perfusion. ActivSight™ provides two modes for assessing tissue perfusion, a dye-less ActivPerfusion™ mode and a dye-mediated ActivICG™ mode. ActivPerfusion™ mode represents a dye-free imaging method using coherent monochromatic light, known as laser speckle contrast imaging (LSCI), to detect blood flow and tissue perfusion. When a red blood cell is illuminated with coherent laser light, a speckle pattern or random interference pattern is created [89]. Because red blood cells are in motion, the speckle pattern fluctuates in time. In areas where there are more red blood cells in motion, the camera will display more blurring of the speckles. The wavelength of light used for LSCI is significantly less important than with imaging methods that rely on contrast absorption because LSCI is solely based on scattering. A limitation of LSCI is motion artifact. The respiratory and cardiac cycles can produce physiologic motion artifacts. However, image

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p­ rocessing methods can compensate and minimize the effect of these artifacts [89–91]. In ActivPerfusion™ mode, tissue perfusion is displayed as a heatmap using a red-green-blue color (RGB) model. Warmer colors in the red spectrum indicate areas of high perfusion, while cooler colors within the blue spectrum indicate areas of relatively less perfusion. There are two imaging displays available within the ActivPerfusion™ mode, overlay and contrast. In the perfusion overlay mode, LSCI perfusion signals from light in the NIR spectrum are viewed over the white light display of the anatomy. The perfusion contrast mode displays only the LSCI perfusion signals to allow finer assessment of tissue perfusion without the interference of colors from the white light spectrum. The ActivICG™ mode uses NIR technology to detect ICG and superimposes the image on tissue in real time. The advantage of the ActivPerfusion™ mode over contrast-based imaging is that the data provided is instantaneous and reproducible. With ActivPerfusion™, the perfusion signal is lost immediately after vessel occlusion. In contrast, if the vessel is transected or occluded after ICG is given, the image will not change due to the presence of residual dye resulting in false-positive data. This represents a pharmacokinetic limitation of ICG and additional perfusion assessments cannot be made until the 3–4-min half-life of ICG has passed [92]. Repeat dosing of ICG is also necessary and the accuracy may be reduced due to the presence of residual ICG.

Transillumination Systems Green Egg—EndoGlow, Rochester, New York, USA Green Egg (Fig.  2.13) was developed as a transillumination device for use in minimally invasive and open surgical procedures. The device contains its own fluorescence polymer which emits NIR when excited by an FGS system. The device is 30 mm in diameter and can be inserted into target tissue areas such as the vagina or rectum. When fluorescence mode is activated on the desired system, transillumination of near-infrared images can be visualized. This device works in a similar manner to fluorophores

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Fig. 2.13 (a) Green Egg—Image courtesy of EndoGlow. (b) Transillumination with use of Green Egg—Photo courtesy of EndoGlow

with emission of NIR light when activated. EndoGlow developed the device, which is pending FDA approval as of November 2021. It utilizes tissue reveal technology which is a fluorescent polymer device used in minimally invasive surgeries via transillumination. The indication for use of Green Egg is for transillumination of anatomic structures to assist in delineating tissue planes, depth, and anatomic borders. It has been used in gynecologic, urologic, and colorectal minimally invasive surgeries. The

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device has clinical use as a vaginal or rectal manipulator that can backlight tissue to enhance tissue visualization. Its use has been beneficial in the visualization and dissection of scarred tissue, reducing rectal injuries in prostatectomies, low anterior resections, and complex hysterectomies [93]. Pilot studies have demonstrated several benefits to the transillumination effect of using a fluorescent manipulator [94]. Surgeons were able to identify deep infiltrating rectal endometriosis, better recognize surgical planes in complex anatomy, and visualize relative tissue depth. The ability to transilluminate vaginal tissue aided in post-hysterectomy bladder dissections during sacrocolpopexies and rectopexies. An unexpected benefit was the increased communication between the attending surgeon and surgical learners (fellows/ residents) or surgical assists. The enhanced visualization allowed the surgical learner or first-assist to see and understand the intricacies of the dissection more easily. Pearls and Pitfalls • Autoclavable device that can be inserted directly into tissue areas (e.g., vagina and rectum). • Sustainable autofluorescence device that obviates the need for dye injection. Infrared Illuminating System (IRIS) Ureteral Kit—Stryker, Kalamazoo, Michigan, USA Infrared Illuminating System (IRIS) Ureteral Kit (Fig. 2.14) is a transilluminating ureteral stent placed intraoperatively to assist in the identification of ureters during minimally invasive and open surgical procedures. This device connects to Stryker’s LED light sources to provide transillumination of the ureter. The L11 LED light source is able to provide excitation at 830 nm transillumination [95, 96]. The device catheters are inserted sterilely via cystoscopy as a ureteral stent at the onset of the case. Catheters are advanced 20 cm in each ureter which is denoted by a double black line on the device. Once the catheters are in place, the emitting diodes are inserted into each catheter until the stopping m ­ echanism on each diode is reached. The IRIS fiber prongs are inserted into

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Fig. 2.14  Infrared Illuminating System Ureteral Kit—Image courtesy of Stryker

the Stryker light source on the far left of the unit. Once the light source is activated, the ureteral stents will illuminate and can be visible in any minimally invasive and open surgery. The ­indication for use of IRIS Ureteral Kit is for the transillumination of ureters to assist in delineating tissue planes during pelvic dissection in both minimally invasive and open surgery. It has been used in gynecologic, urologic, and colorectal surgeries to enhance tissue visualization to help reduce the risk of ureteral injuries [71, 97]. Pearls and Pitfalls • Catheters compatible with guidewires up to 0.038 in. • Catheters from kit can be left in place as needed for use as general use ureteral stents. • IRIS menu on the Stryker’s control unit can toggle IRIS illumination brightness, and the illumination can provide continuous transillumination or pulsating transillumination. Endolumik Fluorescence-Guided Gastric Calibration Tube—Endolumik Inc., Morgantown, West Virginia, USA The Endolumik Fluorescence-Guided Gastric Calibration Tube (Figs.  2.15 and 2.16) is a single-use, fluorescence-guided

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Fig. 2.15  The Endolumik Fluorescence-Guided Gastric Calibration Tube after turning on NIR lighting system, white light view

Fig. 2.16  The Endolumik Fluorescence-Guided Gastric Calibration Tube after turning on NIR lighting system, NIR light view

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calibration tube indicated for use in bariatric, gastric, and esophageal surgery to improve visualization of tube position and to serve as a sizing and measurement guide, for the application of suction, gastric decompression/drainage of gastric fluids, and irrigation and leak testing [98]. This device combines the functionality of a nasogastric or orogastric tube, a calibration tube, and a leak testing system. The device was designed to improve intraoperative visualization and provide surgeons with additional visual cues to identify anatomic structures and delineate tissue planes with the goal of improving the precision of surgical dissection. The Endolumik Gastric Calibration Tube is lit using NIR spectrum LEDs which enable transillumination through esophagogastric tissues. The tube is 80 cm long and is available in two different diameters: 36 and 40 French. It has a rounded tip and small side holes at the distal end to enable gastric decompression and/or irrigation. The proximal end includes a handle with an integral suction regulator. An additional squeeze bulb with pressure gauge may be attached to the end of the regulator to perform leak testing. Pilot studies have been completed using the device to improve visualization during laparoscopic sleeve gastrectomy and laparoscopic gastric bypass (Figs. 2.17, 2.18, and 2.19). The three black stripes at the distal end of the device enable fluorescence-guided measurement of up to 10 cm of length (Fig. 2.20).

Fig. 2.17  Use of the Endolumik Fluorescence-Guided Gastric Calibration Tube during gastric sleeve construction

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Fig. 2.18  Fluorescence-guided gastric sleeve construction during sleeve gastrectomy operation using the Endolumik calibration tube

Fig. 2.19  Fluorescence-guided gastric pouch construction during gastric bypass operation using the Endolumik calibration tube

The device was FDA authorized on March 3, 2023, via the 510K pathway [99] and is also the first device to be authorized through the FDA Safer Technologies Program (STeP), a voluntary program for medical devices that are reasonably expected to significantly improve the safety of currently available treatments.

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Fig. 2.20  Use of the Endolumik Fluorescence-Guided Gastric Calibration Tube to make fluorescence-guided measurements of gastric pouch length during gastric bypass

Pearls and Pitfalls • LED-powered NIR device obviates the need for ICG dye injection. • Compatible with all NIR surgical camera systems. • Combines functionality of orogastric tube, calibration tube, and leak testing system. • Provides fluorescence-guided intraoperative visualization to enable more precise positioning and surgical dissection.

References 1. Yang H, Kim J, Nam W, Kim HJ, Cha IH, Kim D.  Handheld near-­ infrared fluorescence Imaging device using modified action cameras for perioperative guidance of microvascular flap surgery. J Clin Med. 2021;10(3):410. https://doi.org/10.3390/jcm10030410. 2. Frangioni JV.  New technologies for human cancer imaging. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:4012–21. https://doi. org/10.1200/JCO.2007.14.3065.

80

D. Hui et al.

3. Gioux S, Choi HS, Frangioni. Image-guided surgery using invisible near-infrared light: fundamentals of clinical translation. Mol Imaging. 2010;9(5):237–55. https://doi.org/10.2310/7290.2010.00034. 4. Goldstein S, Heaton T, Bondoc A, et al. Evolving applications of fluorescence guided surgery in pediatric surgical oncology: a practical guide for surgeons. J Pediatr Surg. 2021;56(2):215–23. 5. Nagaya T, Nakamura Y, Choyke P, et al. Fluorescence-guided surgery. Front Oncol. 2017;7:314. https://doi.org/10.3389/fonc.2017.00314. 6. DSouza AV, Lin H, Henderson ER, Samkoe KS, Pogue BW. Review of fluorescence guided surgery systems: identification of key performance capabilities beyond indocyanine green imaging. J Biomed Opt. 2016;21(8):80901. 7. Egloff-Juras C, Bezdetnaya L, Dolivet G, Lassalle HP. NIR fluorescence-­ guided tumor surgery: new strategies for the use of indocyanine green. Int J Nanomed. 2019;14:7823–38. https://doi.org/10.2147/IJN.S207486. 8. Nagaya T, Nakamura Y, Choyke P, Kobayashi H. Fluorescence guided surgery. Front Oncol. 2017;7:314. 9. Folli S, Wagnieres G, Pelegrin A. Immunophotodiagnosis of colon carcinomas in patients injected with fluoresceinated chimeric antibodies against carcinoembryonic antigen. Proc Natl Acad Sci U S A. 1992;89(17):7973–7. 10. Namikawa T, Sato T, Hanazaki K.  Recent advances in near-infrared fluorescence-guided imaging surgery using indocyanine green. Surg Today. 2015;45(12):1467–74. https://doi.org/10.1007/s00595-­015-­ 1158-­7. Epub 2015 Mar 29. PMID: 25820596. 11. Barth CW, Gibbs SL. Fluorescence image-guided surgery - a perspective on contrast agent development. Proc SPIE Int Soc Opt Eng. 2020;11222:112220J. https://doi.org/10.1117/12.2545292. 12. Mondal SB, Gao S, Zhu N, et al. Real-time fluorescence image-guided oncologic surgery. Adv Cancer Res. 2014;124:171–211. 13. Chi C, Du Y, Ye J, et al. Intraoperative imaging-guided cancer surgery. Teranostics. 2014;4(11):1072–84. https://doi.org/10.7150/thno.9899. 14. Troyan SL, et al. The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann Surg Oncol. 2009;16:2943–52. 15. National Center for Biotechnology Information. PubChem compound summary for CID 16850, Fluorescein. 2021. https://pubchem.ncbi.nlm. nih.gov/compound/Fluorescein. Accessed 27 Aug 2021. 16. Alander JT, Kaartinen I, Laakso A, Pätilä T, Spillmann T, Tuchin VV, Venermo M, Välisuo P. A review of indocyanine green fluorescent imaging in surgery. Int J Biomed Imaging. 2012;2012:940585. https://doi. org/10.1155/2012/940585. 17. van Manen L, Handgraaf HJM, Diana M, et al. A practical guide for the use of indocyanine green and methylene blue in fluorescence-guided abdominal surgery. Journal of Surg Oncol. 2018;118(2):283–300. https://doi.org/10.1002/jso.25105.

2  Current Fluorescence-Guided Platforms and Devices

81

18. SPY Elite intraoperative perfusion assessment system - operator’s manual. 2015. Accessed Oct 2021. 19. SPY Elite product brochure. 2018. Accessed Oct 2021. 20. SPY Elite intraoperative perfusion assessment system: K182907. 510K approval. 2018. Available: https://www.accessdata.fda.gov/cdrh_docs/ pdf18/K182907.pdf. Accessed Oct 2021. 21. Gurtner GC, Jones GE, Neligan PC, et al. Intraoperative laser angiography using the SPY system: review of the literature and recommendations for use. Ann Surg Innov Res. 2013;7(1):1. https://doi. org/10.1186/1750-­1164-­7-­1. 22. Venturi ML, Mesbahi AN, Copeland-Halperin LR, Suh VY, Yemc L. SPY Elite’s ability to predict nipple necrosis in nipple-sparing mastectomy and immediate tissue expander reconstruction. Plast Reconstr Surg Glob Open. 2017;5(5):e1334. https://doi.org/10.1097/ GOX.0000000000001334. 23. Kislevitz ML, Lu KB, Sanniec K, Amirlak B. Unique uses of SPY: high-­ risk facelift. Plast Reconstr Surg Glob Open. 2019;7(6):e2183. https:// doi.org/10.1097/GOX.0000000000002183. PMID: 31624665; PMCID: PMC6635201. 24. Newman MI, Jack MC, Samson MC.  SPY-Q analysis toolkit values potentially predict mastectomy flap necrosis. Ann Plast Surg. 2013;70(5):595–8. https://doi.org/10.1097/SAP.0b013e3182650b4e. PMID: 23542838. 25. Girard N, Delomenie M, et al. Innovative DIEP flap perfusion evaluation tool: qualitative and quantitative analysis of indocyanine green-­ based fluorescence angiography with the SPY-Q proprietary software. PLoS One. 2019;14:e0217698. 26. Heniford T.  A clinical trial using spy Elite System in planning tissue advancement flaps after ventral hernia repair. ClinicalTrialsgov. 2016. 27. Foppa C, Denoya PI, Tarta C, Bergamaschi R. Indocyanine green fluorescent dye during bowel surgery: are the blood supply “guessing days” over? Tech Coloproctol. 2014;18(8):753–8. https://doi.org/10.1007/ s10151-­014-­1130-­3. Epub 2014 Feb 21. PMID: 24558047. 28. Phillips BT, Fourman MS, Rivara A, Dagum AB, Huston TL, Ganz JC, Bui DT, Khan SU. Comparing quantitative values of two generations of laser-assisted indocyanine green dye angiography systems: can we predict necrosis? Eplasty. 2014;14:e44. PMID: 25525483; PMCID: PMC4258931. 29. Protyniak B, Dinallo AM, Boyan WP Jr, Dressner RM, Arvanitis ML.  Intraoperative indocyanine green fluorescence angiography--an objective evaluation of anastomotic perfusion in colorectal surgery. Am Surg. 2015;81(6):580–4. https://doi.org/10.1177/000313481508100621. PMID: 26031270. 30. Hajiran A, Zekan D, et  al. Use of SPY Elite fluorescence imaging in creation of a continent urinary diversion. Case Rep Urol. 2019;2019:9069841.

82

D. Hui et al.

31. Morozov AO, Alyaev YG, Rapoport LM, Tsarichenko DG, Bezrukov EA, Butnaru DV, Sirota ES. Near-infrared fluorescence with indocyanine green for diagnostics in urology: initial experience. Urologia. 2017;84(3):197–202. https://doi.org/10.5301/uj.5000235. 32. Takahashi M, Ishikawa T, Higashidani K, Katoh H. SPY™: an innovative intra-operative imaging system to evaluate graft patency during off-­ pump coronary artery bypass grafting. Interact Cardiovasc Thorac Surg. 2004;3(33):479–83. 33. Korn JM, Tellez-Diaz A, Bartz-Kurycki M, Gastman B.  Indocyanine green SPY elite-assisted sentinel lymph node biopsy in cutaneous melanoma. Plast Reconstr Surg. 2014;133(4):914–22. https://doi. org/10.1097/PRS.0000000000000006. 34. Vahabzadeh-Hagh AM, Blackwell KE, Abemayor E, St John MA. Sentinel lymph node biopsy in cutaneous melanoma of the head and neck using the indocyanine green SPY Elite system. Am J Otolaryngol. 2018;39(5):485–8. https://doi.org/10.1016/j. amjoto.2018.05.006. 35. SPY PHI - operator’s manual. 2020. Accessed Oct 2021. 36. SPY PHI_SPY-QP booklet supplied by Stryker. 2020. Accessed Oct 2021. 37. SPY PHI system with SPY-PHI fluorescence assessment software: K202244. 510K Approval 2020. Available https://www.accessdata.fda. gov/cdrh_docs/pdf20/K202244.pdf. Accessed Oct 2021. 38. Jakubietz RG, Schmidt K, Bernuth S, Meffert RH, Jakubietz MG. Evaluation of the intraoperative blood flow of pedicled perforator flaps using indocyanine green-fluorescence angiography. Plast Reconstr Surg Glob Open. 2019;7(8):2462. https://doi.org/10.1097/ GOX.0000000000002462. 39. Nguyen JMV, Hogen L, Laframboise S, Bouchard-Fortier G, Ferguson SE, Bernardini MQ, May T. The use of indocyanine green fluorescence angiography to assess anastomotic perfusion following bowel resection in surgery for gynecologic malignancies - a report of 100 consecutive anastomoses. Gynecol Oncol. 2020;158(2):402–6. https://doi. org/10.1016/j.ygyno.2020.05.008. Epub 2020 May 15. PMID: 32423604. 40. pde-neoII (C10935) - operator’s manual. 2016. Accessed Oct 2021. 41. Hamamatsu. PDE-neoII brochure. Available: https://www.hamamatsu. com/resources/pdf/sys/SMES0034E_C10935-­400.pdf. Accessed Oct 2021. 42. Ped-neo: K133719. 510K approval 2014. Available: https://www. accessdata.fda.gov/cdrh_docs/pdf13/K133719.pdf. Accessed Oct 2021. 43. Shikayama T.  Characteristics of the photodynamic eye camera. In: Kusano M, Kokudo N, Toi M, et al., editors. ICG fluorescence imaging and navigation surgery. Tokyo: Springer; 2016. p. 21–7. 44. Tagaya N, Aoyagi H, Nakagawa A, Abe A, Iwasaki Y, Tachibana M, Kubota K.  A novel approach for sentinel lymph node identification

2  Current Fluorescence-Guided Platforms and Devices

83

using fluorescence imaging and image overlay navigation surgery in patients with breast cancer. World J Surg. 2011;35(1):154–8. https://doi. org/10.1007/s00268-­010-­0811-­y. PMID: 20931198 45. Funai K, Kawase A, Shimizu K, Sekihara K, Yamashita T, Shiiya N. Fluorescence navigation with indocyanine green for identification of intersegmental planes using a photodynamic eye camera. J Thorac Dis. 2020;12(9):4817–24. https://doi.org/10.21037/jtd-­20-­1448. 46. Kobayashi K, Kawaguchi Y, Kobayashi Y, Matsumura M, Ishizawa T, Akamatsu N, Kaneko J, Arita J, Sakamoto Y, Kokudo N, Hasegawa K. Identification of liver lesions using fluorescence imaging: comparison of methods for administering indocyanine green. HPB (Oxford). 2021;23(2):262–9. https://doi.org/10.1016/j.hpb.2020.06.006. 47. Chakedis J, Shirley LA, Terando AM, Skoracki R, Phay JE. Identification of the thoracic duct using indocyanine green during cervical lymphadenectomy. Ann Surg Oncol. 2018;25(12):3711–7. https://doi. org/10.1245/s10434-­018-­6690-­4. Epub 2018 Aug 3. PMID: 30076554; PMCID: PMC6181776. 48. Suzuki Y, Sakuma H, Yamazaki S. Comparison of patency rates of lymphaticovenous anastomosis at different sites for lower extremity lymphedema. J Vasc Surg Venous Lymphat Disord. 2019;7(2):222–7. https:// doi.org/10.1016/j.jvsv.2018.10.022. 49. Fluoptics: Fluobeam LX brochure Supplied by Fluoptics. 2021. Available https://fluoptics.us/wp-­content/uploads/2019/10/Fluoptics-­ FluobeamLX-­EN-­web.pdf. Accessed Oct 2021. 50. Fluobeam LX: K190891. 510K approval. 2019. Available. https://www. accessdata.fda.gov/cdrh_docs/pdf19/K190891.pdf. Accessed Oct 2021. 51. Pruimboom T, van Kuijk SMJ, Qiu SS, van den Bos J, Wieringa FP, van der Hulst RRWJ, Schols RM.  Optimizing indocyanine green fluorescence angiography in reconstructive flap surgery: a systematic review and ex  vivo experiments. Surg Innov. 2020;27(1):103–19. https://doi. org/10.1177/1553350619862097. 52. Louges MA, Bellaiche J, Correia N, Chiriac S, François C. Relevance of intraoperative indocyanine green injection in breast reconstruction using DIEP procedure for abdominal scars. Ann Chir Plast Esthet. 2016;61(3):231–4. https://doi.org/10.1016/j.anplas.2016.03.002. 53. Hirche C, Engel H, Kolios L, Cognie J, Hünerbein M, Lehnhardt M, Kremer T. An experimental study to evaluate the Fluobeam 800 imaging system for fluorescence-guided lymphatic imaging and sentinel node biopsy. Surg Innov. 2013;20(5):516–23. https://doi. org/10.1177/1553350612468962. Epub 2012 Dec 27. PMID: 23275469. 54. Demarchi MS, Seeliger B, Lifante J-C, Alesina PF, Triponez F. Fluorescence image-guided surgery for thyroid cancer: utility for preventing hypoparathyroidism. Cancers. 2021;13(15):3792. https://doi. org/10.3390/cancers13153792. 55. Kose E, Kahramangil B, Aydin H, Donmez M, Berber E. Heterogeneous and low-intensity parathyroid autofluorescence: patterns suggesting

84

D. Hui et al.

hyperfunction at parathyroid exploration. Surgery. 2019;165(2):431–7. https://doi.org/10.1016/j.surg.2018.08.006. 56. Demarchi MS, Karenovics W, Bédat B, De Vito C, Triponez F.  Autofluorescence pattern of parathyroid adenomas. BJS Open. 2021;5(1):zraa047. https://doi.org/10.1093/bjsopen/zraa047. 57. Jafari MD, Wexner SD, Martz JE, McLemore EC, Margolin DA, Sherwinter DA, Lee SW, Senagore AJ, Phelan MJ, Stamos MJ. Perfusion assessment in laparoscopic left-sided/anterior resection (PILLAR II): a multi-institutional study. J Am Coll Surg. 2015;220(1):82–92.e1. 58. David G, Mangano A, Dionigi G, Rausei S, Spampatti S, Cassinotti E, Fingerhut A. Clinical applications of indocyanine green (ICG) enhanced fluorescence in laparoscopic surgery. Surg Endosc. 2015;29(7):2046– 55. https://doi.org/10.1007/s00464-­014-­3895-­x. 59. Pinpoint: endoscopic fluorescence imaging system brochure. Supplied by Novadaq. Available. https://www.mirabellmed.at/resources/media/ pinpoint.pdf. Accessed Oct 2021. 60. Pinpoint endoscopic fluorescence imaging system: K182606 510K approval. 2018. Available. https://www.accessdata.fda.gov/cdrh_docs/ pdf18/K182606.pdf. Accessed Oct 2021. 61. Tsutsui N, Yoshida M, Kitajima M, Suzuki Y. Laparoscopic cholecystectomy using the PINPOINT endoscopic fluorescence imaging system with intraoperative fluorescent imaging: a case report. Int J Surg Case Rep. 2016;21:129–32. https://doi.org/10.1016/j.ijscr.2016.02.036. 62. Arthrex SynergyID system instruction for use manual. 2020. Available. https://www.manualslib.com/manual/1868210/Arthrex-­Synergyid-­Ar-­ 3200-­0025.html. Accessed Oct 2021. 63. Synergy ID IR1-000394-en-US_A_IR1-000394 CCU and camera head playsheet Rev2. Supplied by Arthrex. Accessed Oct 2021. 64. Synergy ID FL2-000319-en-­ US_C_SynergyID_Flyer_210x297mm_ web. Supplied by Arthrex. Accessed Oct 2021. 65. Synergy ID IR1-000390_SynergyID augmented reality Playsheet rev 2. Supplied by Arthrex Accessed Oct 2021. 66. Arthrex SynergyID endoscopic imaging system: K202582. 510K approval. 2021. Available https://www.accessdata.fda.gov/cdrh_docs/ pdf20/K202582.pdf. Accessed Oct 2021. 67. Visera Elite II VEII_Borchure_A4_297x210mm_EN_v20 publically available on Olympus. Accessed Oct 2021. 68. Visera Elite II Xenon Light Source. K200542. 510K approval. 2020. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf20/ K200542.pdf. Accessed Oct 2021. 69. 1688 4K camera system with advanced imaging modality user manual. Available at https://5.imimg.com/data5/SELLER/Doc/2021/5/AY/MU/ PK/24888028/stryker-­1688-­endoscopic-­camera.pdf. Accessed Oct 2021. 70. 1688 AIM  - 1588 to 1688 AIM 4K platform justification packet. Supplied by Stryker. Accessed Oct 2021.

2  Current Fluorescence-Guided Platforms and Devices

85

71. Nitta T, Tanaka K, Kataoka J, et al. Novel technique with the IRIS U kit to prevent urethral injury in patients undergoing transanal total mesorectal excision. Ann Med Surg (Lond). 2019;46:1–3. https://doi. org/10.1016/j.amsu.2019.08.002. 72. Storz Image I user manual PDF. Accessed Oct 2021. 73. Image 1S Rubina Brochure. Available. https://www.karlstorz.com/cps/ rde/xbcr/karlstorz_assets/ASSETS/3623282.pdf. Accessed Oct 2021. 74. Rubina: K201399. 510K approval. 2020. Available at https://www. accessdata.fda.gov/cdrh_docs/pdf20/K201399.pdf. Accessed Oct 2021. 75. Image 1S Rubina application in colorectal surgery - supplied by Karl Storz. Available at https://www.karlstorz.com/cps/rde/xbcr/karlstorz_ assets/ASSETS/3646673.pdf. Accessed Oct 2021. 76. Image 1S Rubina application in cholecystectomy  - supplied by Karl Storz. Available at https://www.karlstorz.com/cps/rde/xbcr/karlstorz_ assets/ASSETS/3646675.pdf. Accessed Oct 2021. 77. VS3-Iridium - guide. Available at https://www.medtronic.com/content/ dam/covidien/library/us/en/product/visualisation-­systems/elevision-­ir-­ platform-­ibrochure.pdf. Accessed Oct 2021. 78. Elevision IR brochure. Available at http://www.medtronic.me/content/ dam/covidien/library/us/en/product/visualisation-­systems/elevision-­ir-­ platform-­mis-­brochure.pdf. Accessed Oct 2021. 79. VS3-IR. 510K approval. 2019. Available at https://www.accessdata.fda. gov/cdrh_docs/pdf19/K191851.pdf. Accessed Oct 2021. 80. Hoveling R.  Quest medical imaging. Brochure available at https:// dutchphotonicsevent.nl/wp-­c ontent/uploads/2019/09/Richelle-­ Hoveling-­Making-­the-­invisible-­visible.pdf. Accessed Oct 2021. 81. Artemis handheld imaging system. K191851. 510K approval. 2015. Available https://www.accessdata.fda.gov/cdrh_docs/pdf14/K143474. pdf. Accessed Oct 2021. 82. van Driel PB, van de Giessen M, Boonstra MC, et al. Characterization and evaluation of the artemis camera for fluorescence-guided cancer surgery. Mol Imaging Biol. 2015;17(3):413–23. https://doi.org/10.1007/ s11307-­014-­0799-­z. 83. Wu G. Fluorescence image-guided robotic surgery. In: Liao J, Su LM, editors. Advances in image-guided urologic surgery. New  York, NY: Springer; 2015. https://doi.org/10.1007/978-­1-­4939-­1450-­0_5. 84. DaVinci Xi system user manual - supplied by intuitive. Accessed 2021. 85. DaVinci Firefly imaging system. K141077. 510K approval. 2014. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf14/ K141077.pdf. Accessed 2021. 86. Intuitive; fluorescence imaging for da Vinci X and da Vinci Xi surgical systems provided by intuitive. 2021. 87. Kim J, Ferguson J, Shrand J, Pitt E, et  al. Integrating Firefly fluorescence into image guidance for the da Vinci Robot. SPIE Digital Library; 2021.

86

D. Hui et al.

88. Spinoglio G, Marano A, Formisano G. Robotic surgery using firefly system. In: Dip F, Ishizawa T, Kokudo N, Rosenthal R, editors. Fluorescence imaging for surgeons. Cham: Springer; 2015. https://doi. org/10.1007/978-­3-­319-­15,678-­1_6. 89. Heeman W, Steenbergen W, van Dam GM, Boerma EC. Clinical applications of laser speckle contrast imaging: a review. J Biomed Opt. 2019;24:1. https://doi.org/10.1117/1.jbo.24.8.080901. 90. Richards LM, Towle EL, Fox DJ, Dunn AK. Intraoperative laser speckle contrast imaging with retrospective motion correction for quantitative assessment of cerebral blood flow. Neurophotonics. 2014;1:1. https:// doi.org/10.1117/1.nph.1.1.015006. 91. Lertsakdadet B, Yang BY, Dunn CE, Ponticorvo A, Crouzet C, Bernal N, Durkin AJ, Choi B.  Correcting for motion artifact in handheld laser speckle images. J Biomed Opt. 2018;23:1. https://doi.org/10.1117/1. jbo.23.3.03600. 92. Haller M, Akbulut C, Brechtelsbauer H, Fett W, Briegel J, Finsterer U, Peter K.  Determination of plasma volume with indocyanine green in man. Life Sci. 1993;53:1597–604. https://doi.org/10.1016/0024-­­ 3205(93)90183-­4. 93. Doyle P.  Endoglow tissue reveal technology. Available https://www. endoglow.com/aboutendoglow. Accessed Oct 2021. 94. Panza J, Hernandez D, Gubbels A, Byrnes J. Near infrared fluorescence during minimally invasive sacrocolpopexy: a pilot study. San Antonio, TX: Society of Gynecologic Surgery Video; 2022. 95. AIM (Advanced Imaging Modality) system K 210088. 510K approval 2021. Available at https://www.accessdata.fda.gov/cdrh_docs/pdf21/ K210088.pdf. Accessed Oct 2021. 96. Stryker Infrared Illumination System (IRIS) [AIM light source and ureteral kit]. K151243. 510K approval. 2015. Available at https://www. accessdata.fda.gov/cdrh_docs/pdf15/K151243.pdf. Accessed Oct 2021. 97. Song C, Lee S, Chung H, et al. Case report…using lighted ureteral stent. World J Surg and Surg Res. 2020;3:1262. 98. Towle EL, Richards LM, Kazmi SMS, Fox DJ, Dunn AK. Comparison of indocyanine green angiography and laser speckle contrast imaging for the assessment of vasculature perfusion. Neurosurgery. 2012;71:1023–30. https://doi.org/10.1227/NEU.0b013e31826adf88. 99. https://www.accessdata.fda.gov/cdrh_docs/pdf22/K222880.pdf.

3

Use of Fluorescence Guidance in Colorectal Surgery Michael R. Freund, Anna Duprée, and Steven D. Wexner

Anastomotic Leak Introduction One of the most significant persistent challenges of colorectal surgery is trying to reduce or eliminate the rate of anastomotic leaks (AL). Despite recent advances in technology and surgical technique, AL rates remain between 1% and 19% contingent on the location of anastomosis. The more distal the anastomosis, the

M. R. Freund Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA Department of General Surgery, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel A. Duprée Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany e-mail: [email protected] S. D. Wexner (*) Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL, USA e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 N. Szoka et al. (eds.), The SAGES Manual of Fluorescence-Guided Surgery, https://doi.org/10.1007/978-3-031-40685-0_3

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higher the leak rate: ileocolic (1–8%), colocolonic (2–3%), ileorectal (3–7%), colorectal, or coloanal (5–19%) [1–3]. The anastomosis most prone to AL is a distal pelvic anastomosis, usually performed for low anterior resection (LAR) in patients who were previously treated with neoadjuvant chemoradiotherapy [4]. In these high-risk patients, AL rates can range between 10% and 20% and therefore these patients have been traditionally preemptively diverted with a loop ileostomy. Table 3.1 presents AL rates and reoperation rates for colorectal anastomoses. In addition to the short-term postoperative morbidity, AL is also associated with suboptimal long-­term function and oncologic outcomes including increased local recurrence rates and reduced 5-year survival rates [4, 15, 16]. Stormark et  al. [4] reviewed 22,985 patients from the Swedish, Norwegian, and Danish colorectal cancer registries and showed that five-year relative survival in patients with anastomotic leak was 64.7% compared with 87% for patients with no leak (P 95%. However, a common complication is postoperative hydrocele, which occurs in 20–30% of patients. Lymphatic-sparing surgery is known to reduce the rate of hydrocele and have better andrological outcomes, increasing its use among surgeons. Technically, this

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Fig. 15.11  Intraoperative sentinel lymph node detection during robotic-­ assisted laparoscopic prostatectomy following intraprostatic injection of ICG preoperatively using transrectal ultrasound guidance. (I) Using NIRF-­ laparoscopic D-light angiofluorescence system and (II) using da Vinci TilePro system [31]

involves diluting a vial of ICG (5 mg/dL) with 10 cc sterile water and injection of 2 cc of this solution into the body of the ipsilateral testicle with a 23G needle. This provides almost immediate visualization of lymphatic vessels in near-infrared mode on a laparoscopic camera and green appearance of lymphatics under standard white light mode, allowing for efficient identification and ligation of the spermatic bundle and sparing of lymphatics [34]. Similarly, a combination of both intravenous and subcutaneous injection of ICG for visualization of the spermatic vessels has been described to ensure laparoscopic ligation of only the sper-

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Fig. 15.12  NIRF-guided lymphadenectomy following intraprostatic of ICG during radical prostatectomy [13]

matic veins. To perform this, ICG is dissolved in sterile water at 2.5  mg/mL. 1  mL of this solution is injected intravenously for each desired angiography. The gonadal arterial flow can be visualized about 20–30 s following a shot, and 20 s following that, the gonadal vein is observed. At this concentration and volume, mul-

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tiple angiographies can be performed during dissection with toggling between white light and near-infrared fluorescence to optimize dissection visualization. Lymphatic drainage can be effectively visualized by injection of 1 mL of solution subcutaneously in the desired hemiscrotum prior to cut and another 1 mL about 10 min prior to desired visualization to allow for reliable visualization [35].

Conclusion Herein, we describe use of near-infrared technology in urologic surgery, oncologic and otherwise. Its use in both assessment of ureteral location and viability is crucial for pelvic surgeons and provides a method of limiting ureteral ischemia and minimizing risk of anastomotic strictures in urologic reconstruction. In partial nephrectomy, fluorescence guidance is helpful in identifying hilar vasculature and tumor margins and ensuring tumor and parenchymal ischemia following clamping prior to resection. Direct injection of ICG is imperative in lymph node dissections for nodal identification in urothelial carcinoma and prostatic adenocarcinoma. It is also being used for identification of the neurovascular bundle in nerve-sparing radical prostatectomy. Similarly, ICG can be used for lymphatic-sparing in varicocelectomy to limit the risk of hydrocele postoperatively. The uses of ICG in urologic surgery abound and will only continue to enhance surgical technique and further minimize risk of intra- and postoperative complications.

References 1. Shen JK, Jamnagerwalla J, Yuh BE, Bassett MR, Chenam A, Warner JN, et  al. Real-time indocyanine green angiography with the SPY fluorescence imaging platform decreases benign ureteroenteric strictures in urinary diversions performed during radical cystectomy. Ther Adv Urol. 2019;11:175628721983963. 2. De Nardi P, Elmore U, Maggi G, Maggiore R, Boni L, Cassinotti E, et al. Intraoperative angiography with indocyanine green to assess anastomosis

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perfusion in patients undergoing laparoscopic colorectal resection: results of a multicenter randomized controlled trial. Surg Endosc. 2020;34:53. 3. Kudszus S, Roesel C, Schachtrupp A, Höer JJ. Intraoperative laser fluorescence angiography in colorectal surgery: a noninvasive analysis to reduce the rate of anastomotic leakage. Langenbecks Arch Surg. 2010;395:1025. 4. Hoffmann C, Compton F, Schäfer JH, Steiner U, Fuller TF, Schostak M, et  al. Intraoperative assessment of kidney allograft perfusion by laser-­ assisted Indocyanine green fluorescence videography. Transplant Proc. 2010;42:1526. 5. Karliczek A, Harlaar NJ, Zeebregts CJ, Wiggers T, Baas PC, van Dam GM. Surgeons lack predictive accuracy for anastomotic leakage in gastrointestinal surgery. Int J Color Dis. 2009;24:569. 6. Kaplan-Marans E, Fulla J, Tomer N, Bilal K, Palese M.  Indocyanine green (ICG) in urologic surgery. Urology. 2019;132:10. 7. Olsen TW, Lim JI, Capone A, Myles RA, Gilman JP. Anaphylactic shock following indocyanine green angiography. Arch Ophthalmol. 1996;114:97. 8. Rother U, Gerken ALH, Karampinis I, Klumpp M, Regus S, Meyer A, et al. Dosing of indocyanine green for intraoperative laser fluorescence angiography in kidney transplantation. Microcirculation. 2017;24:1. 9. Keller D, Ishizawa T, Cohen R, Chand M. ICG fluorescence in colorectal surgery: reviewing the current literature, applications, and future direction. Lancet Gastroenterol Hepatol. 2017;2(10):757–66. 10. Bjurlin MA, Gan M, McClintock TR, Volpe A, Borofsky MS, Mottrie A, et  al. Near-infrared fluorescence imaging: emerging applications in robotic upper urinary tract surgery. Eur Urol. 2014;65(4):793–801. 11. Siddighi S, Yune JJ, Hardesty J.  Indocyanine green for intraoperative localization of ureter. Am J Obstet Gynecol. 2014;211(4):436.e1–2. 12. Lee Z, Simhan J, Parker DC, Reilly C, Llukani E, Lee DI, et al. Novel use of Indocyanine green for intraoperative, real-time localization of ureteral stenosis during robot-assisted Ureteroureterostomy. Urology. 2013;82(3):729–33. 13. Cacciamani GE, Shakir A, Tafuri A, Gill K, Han J, Ahmadi N, et al. Best practices in near-infrared fluorescence imaging with indocyanine green (NIRF/ICG)-guided robotic urologic surgery: a systematic review-based expert consensus. World J Urol. 2020;38(4):883–96. 14. Borofsky MS, Gill IS, Hemal AK, Marien TP, Jayaratna I, Krane LS, et al. Near-infrared fluorescence imaging to facilitate super-selective arterial clamping during zero-ischaemia robotic partial nephrectomy. BJU Int. 2013;111:604. 15. Hsu M, Gupta M, Su LM, Liao JC. Intraoperative optical imaging and tissue interrogation during urologic surgery. Curr Opin Urol. 2014;24:66. 16. Mitsui Y, Shiina H, Arichi N, Hiraoka T, Inoue S, Sumura M, et  al. Indocyanine green (ICG)-based fluorescence navigation system for dis-

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crimination of kidney cancer from normal parenchyma: application during partial nephrectomy. Int Urol Nephrol. 2012;44:753. 17. Angell JE, Khemees TA, Abaza R. Optimization of near infrared fluorescence tumor localization during robotic partial nephrectomy. J Urol. 2013;190(5):1668–73. 18. Manny TB, Krane LS, Hemal AK.  Indocyanine green cannot predict malignancy in partial nephrectomy: histopathologic correlation with fluorescence pattern in 100 patients. J Endourol. 2013;27:918. 19. Shao P, Qin C, Yin C, Meng X, Ju X, Li J, et  al. Laparoscopic partial nephrectomy with segmental renal artery clamping: technique and clinical outcomes. Eur Urol. 2011;59:849. 20. Alfred Witjes J, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM, et al. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2017;71:462. 21. Manny TB, Hemal AK.  Fluorescence-enhanced robotic radical cystectomy using unconjugated indocyanine green for pelvic lymphangiography, tumor marking, and mesenteric angiography: the initial clinical experience. Urology. 2014;83:824. 22. Cahill RA, Ris F, Mortensen NJ. Near-infrared laparoscopy for real-time intra-operative arterial and lymphatic perfusion imaging. Color Dis. 2011;13:12. 23. Harke NN, Godes M, Wagner C, Addali M, Fangmeyer B, Urbanova K, et al. Fluorescence-supported lymphography and extended pelvic lymph node dissection in robot-assisted radical prostatectomy: a prospective, randomized trial. World J Urol. 2018;36:1817. 24. KleinJan GH, van den Berg NS, de Jong J, Wit EM, Thygessen H, Vegt E, et al. Multimodal hybrid imaging agents for sentinel node mapping as a means to (re)connect nuclear medicine to advances made in robot-­ assisted surgery. Eur J Nucl Med Mol Imaging. 2016;43:1278. 25. Wit EMK, Acar C, Grivas N, Yuan C, Horenblas S, Liedberg F, et  al. Sentinel node procedure in prostate cancer: a systematic review to assess diagnostic accuracy. Eur Urol. 2017;71:596. 26. Anderson CB, Morgan TM, Kappa S, Moore D, Clark PE, Davis R, et al. Ureteroenteric anastomotic strictures after radical cystectomy—does operative approach matter? J Urol. 2013;189:541–7. 27. Davis NF, Burke JP, McDermott T, Flynn R, Manecksha RP, Thornhill JA.  Bricker versus Wallace anastomosis: a meta-analysis of ureteroenteric stricture rates after ileal conduit urinary diversion. Can Urol Assoc J. 2015;9:284. 28. Doshi CP, Wozniak A, Quek ML. Near-infrared fluorescence imaging of ureters with intravenous Indocyanine green during radical cystectomy to prevent ureteroenteric anastomotic strictures. Urology. 2020;144:220. 29. Ahmadi N, Ashrafi AN, Hartman N, Shakir A, Cacciamani GE, Freitas D, et al. Use of indocyanine green to minimise uretero-enteric strictures after robotic radical cystectomy. BJU Int. 2019;124(2):302–7.

462

D. Zekan et al.

30. Jafari MD, Wexner SD, Martz JE, McLemore EC, Margolin DA, Sherwinter DA, et  al. Perfusion assessment in laparoscopic left-sided/ anterior resection (PILLAR II): a multi-institutional study. J Am Coll Surg. 2015;220:82. 31. Van Der Poel HG, Buckle T, Brouwer OR, Valdés Olmos RA, Van Leeuwen FWB. Intraoperative laparoscopic fluorescence guidance to the sentinel lymph node in prostate cancer patients: clinical proof of concept of an integrated functional imaging approach using a multimodal tracer. Eur Urol. 2011;60:826. 32. Kumar A, Samavedi S, Bates A, Coelho R, Rocco B, Marquinez J, et al. Using Indocyanine green and near-infrared fluorescence technology to identify the “landmark artery” during robot-assisted radical prostatectomy. Videourology. 2015;29:1. 33. Mangano M, Gobbi A, Beniamin F, Lamon C, Ciacci M, Maccatrozzo L. Robot-assisted nerve-sparing radical prostatectomy using near-­infrared fluorescence technology and indocyanine green: initial experience. Urolo J. 2018;85(1):29–31. 34. Esposito C, Turrà F, Del Conte F, Izzo S, Gargiulo F, Farina A, et  al. Indocyanine green fluorescence lymphography: a new technique to perform lymphatic sparing laparoscopic palomo varicocelectomy in children. J Laparoendosc Adv Surg Tech. 2019;29(4):564–7. 35. Fukui K, Saito T, Fuchimoto Y. Pediatric laparoscopic varicocelectomy using indocyanine green (ICG) fluorescence imaging. J Pediatr Surg Case Rep. 2021;67:101818. 36. Rother U, Amann K, Adler W, Nawroth N, Karampinis I, Keese M, et al. Quantitative assessment of microperfusion by indocyanine green angiography in kidney transplantation resembles chronic morphological changes in kidney specimens. Microcirculation. 2019;26:e12529. 37. Sekijima M, Tojimbara T, Sato S, Nakamura M, Kawase T, Kai K, et al. An intraoperative fluorescent imaging system in organ transplantation. Transplant Proc. 2004;36:2188–90. 38. Borofsky MS, Gill IS, Hemal AK, Marien TP, Jayaratna I, Krane LS, et al. Near-infrared fluorescence imaging to facilitate super-selective arterial clamping during zero-ischaemia robotic partial nephrectomy: near-­ infrared fluorescence imaging in zero ischaemia RPN.  BJU Int. 2013;111(4):604–10.

Use of Fluorescence Guidance in Gynecology

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Lioudmila Lipetskaia, Barbara Diane Gillis, and Courtney Griffiths

Introduction Gynecological surgery in the United States comprises about 25% of inpatient surgical procedures for women over the last 20 years, with 64% classified as solely obstetric, 29% as solely gynecologic, and 7% as both [1]. Up to one third of all women in the United States undergo hysterectomy by age 60 [2]. This massive surgical field is also growing with the increased incidence of gynecologic cancer, specifically endometrial cancer whose rates have steadily risen since the 1990s [3]. Endometrial cancer is closely linked with obesity, with approximately 57% of endome-

L. Lipetskaia (*) Division of Urogynecology, Department of Obstetrics and Gynecology, Cooper Medical School for Rowan University, Camden, NJ, USA e-mail: [email protected] B. D. Gillis West Virginia University School of Medicine, Morgantown, WV, USA e-mail: [email protected] C. Griffiths Division of Gynecology Oncology, Cooper Medical School for Rowan University, Camden, NJ, USA e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 N. Szoka et al. (eds.), The SAGES Manual of Fluorescence-Guided Surgery, https://doi.org/10.1007/978-3-031-40685-0_16

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trial cancers in the United States attributable to obesity [4]. ­Therefore, gynecological surgery for both benign and oncologic cases will likely continue to grow. Fluorescence-guided surgery (FGS) is on the forefront of medicine with at least 85 clinical trials in the United States, and numerous applications already implemented across the world [5]. Fluorescence-guided surgery utilizes fluorescent dye or a nearinfrared emitting light source to identify anatomic structures during surgical procedures. This chapter will describe uses of FGS in gynecologic oncology for lymphatic mapping, sentinel lymph node identification, and tumor margin detection, and in benign gynecology, for the management of endometriosis and during complex pelvic reconstruction, as well as for improving identification of anatomical structures and augmenting intraoperative navigation.

 isease-Specific Applications of Fluorescence D Imaging Gynecologic Oncology  umor Lymphatic Imaging in Gynecologic Cancers T Endometrial cancer (EC): Indocynanine Green (ICG) dye is clinically used to monitor the lymphatic vessels and sentinel lymph nodes (SLN) of uterine tumors [6]. It can reduce lymphedema and other associated morbidities to selectively remove SLNs which can prevent tumor metastasis. ICG improved the detection rate of pelvic SLN compared to conventional dyes and may be considered as the superior technique [7]. In clinical practice, the rate of systematic LND further decreased after incorporating SLN mapping with ICG.  The National Comprehensive Cancer Network (NCCN) recommends fluorescent SLN mapping for endometrial cancer by cervical ICG injection directly [8]. The NCCN guidelines have approved sentinel node localization as a staging technique for EC, as grade 2B evidence. Prospective and retrospective clinical studies have shown that sentinel lymph node mapping (SLNM) combined with pathologic ultra-staging has satisfactory detection rate, sensitivity, and negative predictive value of SLN in

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patients with early low-risk endometrial ­carcinoma and does not affect progression-free and overall survival rates. However, the prognostic effect of SLN mapping in high-risk EC patients still needs to be further verified by larger studies. In the earlier version, NCCN guidelines suggested SLN mapping should be cautious for high-risk EC patients. In the latest version, it is believed that SLN mapping may also have a high detection rate and diagnostic accuracy in high-risk EC. Pelvic/para-aortic sentinel lymph nodes were three times more likely to be extracted than nonSLNs, providing accurate staging for optimized postoperative patient management [8]. To date, no published randomized study has investigated the survival benefit. Therefore, although the use of ICG and fluorescent detection cameras is considered the most appropriate for obtaining the best detection rates in lymphatic mapping in endometrial cancer, the SLN technique still is considered as experimental (Fig. 16.1). Imaging techniques: 1.25  mg/mL concentration, 4  mL (1  mL deep and 1 mL superficial), was injected into the cervix (3 and 9 o’clock position) with 10  min waiting time before dissection. Alternatively, ICG can be injected into tumor directly (via hysteroscopy) or fundally/subserosally. The latter approach increases para-­ aortic LN detection rate but decreases pelvic LN detection rate and can lead to intraabdominal dispersion of the dye [9] (Fig. 16.2). Cervical cancer: Cervical cancer is not as prevalent as endometrial cancer, and data on SLN mapping is limited and frequently derived from the studies analyzing SLN detection in cases of cer-

Fig. 16.1  Endometrial cancer: right obturator sentinel lymph node regular light (left) and infrared light (right)

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Fig. 16.2  High-resolution image of para-aortic sentinel lymph node mapping for endometrial cancer during robotic LND

vix and endometrial cancer. The assumption is made that ­migration to the pelvic nodes is similar in both cancers. With this caveat, the studies demonstrate the effectiveness of ICG during SLN biopsy using robotic, laparoscopic surgery and laparotomy, concluding that the method is feasible, safe, time-efficient, and seemingly reliable for lymphatic mapping in early-stage cervical cancer [10]. Two-meta-analyses concluded that in cervical and endometrial cancer, ICG SLN-mapping seems to be equivalent or superior to the conventional dyes [11, 12]. Imaging technique: No standardized technique was reported. Concentrations of ICG have ranged from 0.5 to 5.0 mg/mL, and injected volumes have varied from 0.2 to 4.0  mL.  The study in healthy female pigs identified 250–500 μg ICG dose as optimal in identification of a SLN with more distinction from the surrounding tissues [13]. Cervix is injected in 2–4 quadrants (12, 3, 6, and

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9 h or 3 and 9). Slow injection is recommended to prevent damage to lymphatic vessels. Optimal time for starting dissection is unclear. In the studies, the median time between injection and the start of dissection is approximately 30 min. Vulvar cancer: In the vulva bilateral SLN sampling should be assured in central tumors only. If tumor is located at least 1 cm lateral to the clitoris, unilateral dissection is sufficient. A standard technique for dissection involves the use of double tracer (blue dye and Tc-99 m-labeled radiocolloid) and requires a lymphoscintigraphy. The use of ICG in vulvar cancer is limited as near-­ infrared (NIR) fluorescence can detect targets up to 5–8 mm deep [14]. A deeper target at 25 mm would be invisible by NIR fluorescence imaging alone; hence, majority studies combine NIR fluorescence imaging with radioscintigraphy which enables visualization of deeper inguinal SLNs, especially in patients with obesity. The robotic video endoscopy inguinal lymphadenectomy is emerging technique for diagnosis of vulvar cancer, but so far only one case report with SLN mapping with ICG followed by systematic inguinal lymphadenectomy is described [15]. So far, the best results in mapping are achieved using a combination of ICG and technetium-99 m nanocolloid. Once overlying tissue is removed, as guided by radioscintigraphy, NIR fluorescence is used for more precise image guidance to compensate for relatively poor spatial and temporal resolution of radioscintigraphy. Body mass index seems to be a limitation for using ICG alone as a tracer. Imaging technique: Concentration of 0.5/2.5 mg/mL. A total of 4  mL (1  mL at 4 sites) was injected directly into the tumor (intracutaneously) with dissection starting in 10 min. Alternatively, ICG can be injected around the scar at prior excision site in case of cancer recurrence. Ovarian cancer (OC): The incidence of lymph node metastases in early OC ranges between and 30%, and pelvic and paraaortic lymphadenectomy is recommended. In early ovarian cancer, lymph node metastases are found as isolated para-aortic nodes in 50% of patients, as isolated pelvic nodes in 20% of patients, and

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in both in the remaining 30% of patients [16]. The three major ovarian lymphatic drainage pathways (infundibulopelvic ligament, the ovarian ligament, and the round ligament) explain the wide geography of the metastatic disease and point out to the potential injection sites for tracers. So far, two ongoing prospective, multicenter studies attempt to determine efficacy and safety of ICG in SLN mapping. Both SELLY (SLN in early-stage ovarian cancer) and SENTOV ((sentinel lymph node technique in ovarian cancer) evaluate ICG in conjunction with Tc-99 m. The Tc-99 m remains trapped in the lymph nodes for a long period and is injected before the oophorectomy. The small ICG molecule migrates rapidly through lymphatic vessels and makes it difficult to accurately identify the first node; hence, ICG is injected after an ovary is removed. The preliminary data from SELLY and SENTOV concluded that SLN mapping in early-stage ovarian cancer is feasible without major intraoperative or safety concerns [17] [18]. The data on accuracy and detection rate of this technique is not available yet; hence, no recommendation can be given because this procedure still is experimental. Imaging technique: Concentration of 1.25 mg/mL. A total of 0.5–1  mL was injected into infundibulopelvic and ovarian ligament with dissection starting almost immediately. Alternative injection sites are mesovarium, hilum of the ovary, and ovarian cortex.

 umor Margin Detection T Free surgical margin is the main challenge in vulvar and vaginal cancer surgery. In solid tumors, incomplete surgery results in high risk of tumor recurrence. The real-time detection of tumor margins helps achieve complete resection and decrease risk of recurrence. Case reports present ICG use in vulvar and vaginal cancer for surgical resection guidance. In the first case after primary incomplete resection of vulvar cancer, an intravenous ICG injection determined the free margin after resection. In the second case, peritumoral ICG injection 1  cm around the upper vagina cancer showed a clear resection margin on the final pathological finding after robotic colpo-hysterectomy with LND [19].

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Imaging technique: For vulvar cancer, 2 cc of diluted ICG IV immediately before surgery and for vaginal cancer, 2 mL peritumoral injection with 1 cm radius. No uterine manipulator is used, and a vaginal probe is inserted to develop the fornix. Techniques need to be validated on a large scale.

 anagement of Bowel and GU Anastomosis as a Part M of Cytoreductive Surgery Several patient and surgical factors influence the risk of anastomotic leak after bowel resection during pelvic exenteration. Surgeons typically rely on subjective methods to identify anastomotic leaks such as palpation of vessels and assessment of tissue vitality in white light. The addition of intraoperative ICG assessment of colorectal anastomoses demonstrated reduced risk of anastomotic leakage in treatment of GI malignancies in ten studies. In seven studies, resection of the colon or rectum was extended into more vital tissue if ICG detected an insufficient perfusion at the proposed anastomosis site. Three studies concluded that ICG perfusion assessment reduced the risk of anastomotic leakage significantly. One study found no difference in anastomotic leakage rate between the control group and the ICG group [20]. This concept was adopted in the management of anastomosis in gynecologic cancers requiring wide organ resection as a part of cytoreduction strategy. ICG was used to evaluate perfusion of ileum-ileum, right and left ureter with small bowel, and colorectal sides of anastomosis to assess vascularity of urinary diversion after pelvic exenteration for gynecologic cancers (Fig. 16.3). Out of 15 subjects, 3 patients had postoperative complications due to poor perfusion of anastomosis (ureteral and ileal anastomosis leaks and ureteric stricture); all these cases had a suboptimal intraoperative ICG perfusion [21] (Fig. 16.4). Imaging technique: IV ICG bolus before and/or after anastomosis construction 0.2–0.5  mg/kg (total ranging from 0.2 to 0.5 mg/kg). In order to achieve a more objective perfusion assessment, scoring systems were developed and intraoperative pixel brightness analysis was performed. Unfortunately, the quantification did not lead to a cutoff value.

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Fig. 16.3  Bricker ileal conduit uretero-enteric anastomoses demonstrating right ureter with optimal indocyanine green (ICG) perfusion (+++) vs. left ureter with poor ICG perfusion (− − -). (Bizzai et al. Indocyanine Green to Assess Vascularity of Ileal Conduit Anastomosis During Pelvic Exenteration for Recuent/Persistent Gynecological Cancer: A Pilot Study. Front Oncol. 2021 Dec 7;11:727725. doi: 10.3389/fonc.2021.727725. PMID: 34950574; PMCID: PMC8691262)

Surgical Management of Endometriosis  etection of Endometriotic Lesions D Endometriosis has three clinical forms: peritoneal superficial endometriosis, ovarian endometriosis and deeply infiltrating endometriosis in the rectovaginal septum [22]. Identifying endometriosis lesions may be challenging due to variable appearances, small size, and concealed localization. ICG green highlights the location of endometriotic lesions as they are associated with increased areas of vascularization and inflammation. The endometriotic lesion patterns observed during surgery are described as diffuse or abundant fluorescence (hypervascular pattern) in 40% women and poor or absent (hypovascular pattern) in 60% women with endometriosis. Although some studies report excellent sensi-

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Fig. 16.4  Transabdominal anastomotic perfusion assessment using the SPY-­ PHI system (Stryker, USA). (a) Transabdominal perfusion assessment showing well-perfused bowel. (b) Transabdominal perfusion assessment showing perfusion defect (Nguyen JMV et al. The use of indocyanine green fluorescence angiography to assess anastomotic perfusion following bowel resection in surgery for gynecologic malignancies – A report of 100 consecutive anastomoses. Gynecol Oncol. 2020 Aug;158 (2):402–406. Doi: 10.1016/j. ygyno.2020.05.008. Epub 2020 May 15. PMID: 32423604)

tivity and specificity in identifying the lesions, others conclude that the single use of ICG shows no improvement in the detection of endometriosis [22]. It appears that ICG performs better in providing demarcation of deep endometriotic lesions assisting with more complete resection, but its diagnostic value is controversial. Imaging technique: 0.25  mg/kg ICG i.v. with time intervals varying between a minimum of 5 and a maximum of about 30 min.

 anagement of Bowel Involvement During Surgery M for Endometriosis ICG green is used to evaluate the bowel vascularization after endometriosis rectal shaving surgery. Separating the healthy rectal tissue from the rectovaginal deep nodules aids in decision whether to enlarge the resection to the posterior vaginal fornix [23]. Deep lesion excision and rectal shaving techniques required for successful endometriosis treatment can jeopardize rectal wall integrity and lead to rectovaginal fistula formation. Visual assessment of the rectal shaving area is labeled as fluoresced with the visual Likert-type scale. Oversewing of rectal muscularis is performed if there is a concern for rectal tissue integrity (Fig. 16.5).

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Fig. 16.5  Coagulated tissue appears dark and non-perfused in the area where rectal shaving was performed (Bar-Shavit Y, et all Use of indocyanine green in endometriosis surgery. Fertil Steril. 2018 Jun;109 (6):1136–1137. doi: 10.1016/j.fertnstert.2018.02.113. Epub 2018 Jun 6. PMID: 29885885)

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The RCT study is underway to assess if this technique leads to decrease fistula formation [24]. Another study demonstrated that when full-thickness bowel resection is necessary for nodule excision, ICG perfusion mapping can be performed in the same manner as in colorectal surgery [25]. Imaging technique: A IV bolus of 0.2 mg/kg of indocyanine green after dilution (2.5 mg/mL) at the end of a rectal shaving.

Complex Pelvic Reconstructive Procedures  emarcating Retropubic Space Anatomy in Burch D Colposuspension Retropubic colposuspension is a surgical treatment which involves lifting the tissues near the bladder neck and proximal urethra and attaching them to Cooper’s ligament in attempt to treat stress urinary incontinence. Procedure is traditionally performed via open approach and tension of the sutures attaching vagina to Cooper’s ligament adjusted by palpation. With advent of robotic surgery and lack of haptic feedback, new methods of tension adjustment are needed. Bladder neck can be identified by tagging on Foley balloon inserted into the bladder and inflated with 30 cc of ICG tinged medium. Foley balloon highlighted by ICG demarcates bladder wall from underlying vaginal tissue plain allowing for more precise dissection and adequate suspension suture. Imaging technique: 100  cc of intralipid TPN solution mixed with 0.5  mL of ICG green (2.5  mg/mL in distilled water) and 30 cc instilled in 18F Foley balloon inserted into the bladder [26].  eovagina Construction in Congenital Anomalies N and Transgender Surgery Patients with vaginal agenesis undergo vaginoplasty using a mold that had been wrapped with skin graft (McIndoe technique) or external traction device placed over the abdominal wall (Vecchietti procedure). Trans-female patients might require laparoscopic sigmoid vaginoplasty if standard penile-scrotal flap inversion technique is not feasible. In either case, creation of neovagina is a highly complex surgery requiring meticulous dissection of com-

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plex anatomical spaces. ICG can be used intraoperatively in laparoscopic sigmoid vaginoplasty to determine sigmoid segment perfusion and viability prior to committing to neovagina construction. In the study of five patients, ICG green demonstrated poor viability of sigmoid segment in one patient and procedure was aborted [27]. In another study, ICG green was helpful in identifying upper urinary tract anatomy, thus guiding safer and faster dissection during Vecchietti procedure [28]. Imaging technique: Cystoscopic intraureteral ICG injection lasted 3.4 min, improving the anatomic identification of the ureters, with the additional benefit of having the bladder highlighted in case of congenital anomaly.

 evisions of Prior Reconstructive Surgeries R Frequently pelvic reconstructive procedures use permanent grafts (polypropylene mesh or Gore-Tex sutures) to increase longevity of the repair and prevent prolapse or incontinence recurrence. Although the risks of complications associated with graft use are low, occasionally excision of permanent materials from pelvic structures is required to treat graft related complications. In case of erosion or infections due to foreign body, it is important to minimize the damage to adjacent organs while dissecting implant away from vagina. The tissue planes are frequently distorted due to inflammation and scarring, and highlighting adjacent structures with the ICG helps to delineate the tissue planes and prevent injury (Fig. 16.6).

Fig. 16.6  Revision of prior pelvic reconstructive surgery complicated by Gore-Tex suture erosion (Parts a–c) (a) Attempt to remove Gore-Tex stitch eroding in vagina. Stitch is located in the area of vagina adjacent to left ureterovesical junction. (b) Foley balloon filled with ICG mix enhances bladder visualization. (c) Foley balloon manipulated with robotic instruments into the area of left ureterovesical junction allows to safely continue dissection avoiding injury to bladder and ureter

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Imaging technique: 100  cc of intralipid TPN solution mixed with 0.5  mL of ICG green (2.5  mg/mL in distilled water) and 30 cc instilled in 18F Foly balloon inserted into bladder.

Fluorescent Angiography  aginal Cuff Angiography in an Attempt to Assess V Devascularization Due to Thermal Injury After Total Robotic Hysterectomy Minimally invasive hysterectomy compares favorably to laparotomy in overall complication rate but is notorious for increased vaginal cuff dehiscence. Both energy used during colpotomy and suturing techniques for cuff closure were implicated in higher dehiscence rate [29]. Vascular perfusion plays a role in cuff healing along with other factors. Developing techniques for quantification of thermal damage impact on perfusion can come in handy while we are attempting to find solutions for this problem. ICG angiography represents an emerging technology for real-time evaluation of the vaginal cuff during laparoscopic hysterectomy with potential to limit the incidence of vaginal cuff dehiscence through design of further research studies. Imaging technique: 2.5–5 mg ICG IV bolus followed by 10 mL saline flash. ICG dye appeared in surgical field in 11 s. Repeated administration was required in 11  min. Most participants show fluorescence all the way to the cuff edge, but the width of thermal injury brim varies around the cuff. The calculation of cuff perimeter percentage with adequate perfusion is required to assess the extent of devascularized zone [30] (Fig. 16.7).

Ovarian Artery Perfusion to Assess Ovarian Torsion Ovarian torsion is defined as partial or complete rotation of the ovarian vascular pedicle and causes obstruction to venous outflow and arterial inflow. It presents as acute abdominal pain and ­diagnosed during surgical exploration. The ultimate goal of sur-

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Fig. 16.7  Samples of images used for perfusion analysis (a, b) with representative markings demonstrating adequate perfusion (c, d) at the cuff. The short perpendicular bars delineate transition from perfused to nonperfused regions. The parallel curve demonstrates areas with adequate perfusion. The long perpendicular bars in D delineate the total length of the closed vaginal cuff (Beran et al Laser Angiography with Indocyanine Green to Assess Vaginal Cuff Perfusion during Total Laparoscopic Hysterectomy: A Pilot Study. J Minim Invasive Gynecol. 2017 Mar-Apr;24 (3):432–437. doi: 10.1016/j. jmig.2016.12.021. Epub 2017 Jan 4. PMID: 28063908)

gery is restoration of blood flow to the ovary and ovarian preservation whenever possible. Potential viability of torsed ovary is traditionally assessed visually by observing twisted and blackand-blue adnexa, and decision on surgical removal needs to be made in real time. One study assessed feasibility of ICG use in diagnosis of detorsed adnexa viability. Perfusion was achieved in ten patients (83%) in a median time of 1 min, resulting in ovarian conservation. Perfusion was absent in two cases, and post-­ oophorectomy histologic necrosis was confirmed in one case [31]. Imaging technique: A loading dose of 8  cc of ICG dye was injected IV and untwisted ovary was observed for 10  min after ICG dye administration. Perfusion was defined as visualization of ICG dye in the involved ovary and/or fallopian tube, causing the structures to turn green. If no perfusion was visualized 10  min after the initial bolus injection, an additional 4 cc bolus of ICG

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dye could be administered, and the ovary was observed for another 10 min. This process could be repeated an additional three times, if necessary, resulting in a maximum volume of 20 cc of ICG dye.

 luorescence Imaging-Guided Surgical F Navigation Ureter Visualization Iatrogenic bladder injuries are the most frequent urologic injuries, but they are usually recognized and repaired immediately, and potential complications are typically minor. In contrast, 50–70% of iatrogenic ureteral injuries are diagnosed postoperatively with gynecologic surgery accounting for 52% to 82% of those injuries [32]. The ureter is injured in roughly 0.5–2% of all hysterectomies and routine gynecologic pelvic operations [33, 34]. The lack of precise haptic feedback in robotic and laparoscopic surgery has previously been associated with increasing rates of inadvertent ureteral injuries across various surgical specialties [35]. Clear identification of the pelvic ureter can be difficult but remains essential to avoid inadvertent iatrogenic ureteral injury. The preventative ureteral stents placement is controversial in gynecological surgery due to the lack of clear evidence of efficacy. Illuminating catheters have been designed to improve visualization of ureters intraoperatively but did not gain popularity [36]. Injection technique: Three techniques involving NIR entail IV use of NIR dye, direct instillation of NIR solution into ureteral orifice via cystoscopy, and use of ureteral catheter with NIR properties in construction material. (a) 0.06 mg/kg of nerindocianine sodium administered IV. Ureter is imaged at 10 and 30 min post-infusion. Lower (0.042 mg/ kg) and higher (0.12 mg/kg) doses perform poorer by diminishing visualization time or decreasing the efficacy [37] (Fig. 16.8). (b) Cystoscopy is performed at the beginning of the surgery to insert the tip of a 6-Fr ureteral catheter and instill 8  mL of

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Fig. 16.8  A. Intraoperative ureteral identification by nerindocianine sodium use via IV administration (Huh et al. Fluorescence Imaging of the Ureter in Minimally Invasive Pelvic Surgery. J Minim Invasive Gynecol. 2021 Feb;28(2):332–341.e14. doi: 10.1016/j.jmig.2020.06.022. Epub 2020 Jun 29. PMID: 32615331)

ICG (1.25 mg/mL solution). Finally, the catheters are removed because the fluorescence remains in the ureters up to 6 h. This method can be applied retroactively if injury is suspected at the end of surgery. Ureteral injury is identified by observing extravasation of the dye after instillation (Fig. 16.9). (c) The ureteral catheter constructed with near-infrared dye similar to ICG embedded in its wall does not require intraoperative dye administration. This technique is user- friendly and can be utilized by the novice surgeons with little experience in laparoscopic surgery [38] (Fig. 16.10).

Fluorescent Medical Devices By creating medical and surgical devices that fluoresce under NIR imaging, the number of patients benefiting from fluorescence assisted surgery will increase. There are a few medical device companies (EndoGlow, Rochester, NY.) that have been innovative in developing surgical devices that fluoresce under NIR imaging (Fig. 16.11). For instance, fluorescent imbedded rectal and vaginal manipulators take the place of traditional bougies or end-to-­ end anastomosis sizers in pelvic surgeries. Pilot studies have

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Fig. 16.9  Intraoperative ureteral identification by indocyanine green use via catheter infusion (Shibata R et  al. Intraoperative dyes, fluorescence and enhanced imaging in benign gynaecologic surgery. Cu Opin Obstet Gynecol. 2022 Aug 1;34 (4):237–243. doi: 10.1097/GCO.0000000000000793. PMID: 35895966)

Fig. 16.10  Intraoperative ureteral identification by indocyanine green use via NIR-embedded novel ureteral catheter infusion (Fujita H, et al. Use of a Novel Fluorescent Catheter to Locate the Ureters during Total Laparoscopic Hysterectomy. J Minim Invasive Gynecol. 2021 Jul;28 (7):1420–1424. doi: 10.1016/j.jmig.2021.04.004. Epub 2021 Apr 19. PMID: 33887490)

demonstrated several benefits to the transillumination effect of using a fluorescent manipulator [39]. Surgeons were able to identify deep infiltrating rectal endometriosis, better recognize surgical planes in complex anatomy, and visualize relative tissue depth. The ability to transilluminate vaginal tissue aided in post-­

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hysterectomy bladder dissections during sacrocolpopexies and rectopexies. An unexpected benefit was the increased communication between the attending surgeon and surgical learners ­(fellows/residents) or surgical assists. The enhanced visualization allowed the surgical learner or first-assist to see and understand the intricacies of the dissection more easily. The manipulator can be placed in the vagina (Fig.  16.11) or rectum (Fig.  16.12) to manipulate tissue and highlight tissue plains, therefore guiding dissection.

Fig. 16.11  EndoGlow device placed into vagina to guide dissection between vagina and bladder (regular light view on left and infrared view on the right)

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Fig. 16.12  EndoGlow device placed into rectum to guide dissection between rectum and closed vaginal cuff after hysterectomy (regular light view on left and infrared view on the right)

Conclusion FGS has numerous clinical applications in gynecological surgery from SLN mapping, anatomic visualization of ureters or tissue planes, and perfusion assessment of anastomoses or specific arteries. These tools aid surgeons intraoperatively in real time and provide essential visual feedback that has previously been inaccessible. FGS continues to rapidly evolve and improve surgical care; however, further well-powered studies are needed to establish the value of fluorescence guidance in gynecologic surgery.

References 1. Oliphant SS, Jones KA, Wang L, Bunker CH, Lowder JL. Trends over time with commonly performed obstetric and gynecologic inpatient procedures. Obstet Gynecol. 2010;116(4):926–31. https://doi.org/10.1097/ AOG.0b013e3181f38599. 2. Gupta S, Maghsoudlou P, Ajao M, Einarsson JI, King LP. Very low rates of ureteral injury in laparoscopic hysterectomy performed by fellowship-­ trained minimally invasive gynecologic surgeons. J Minim Invasive Gynecol. 2022;29(9):1099–103. 3. Towner M, Kim JJ, Simon MA, Matei D, Roque D. Disparities in gynecologic cancer incidence, treatment, and survival: a naative review of outcomes among black and white women in the United States. Int J Gynecol Cancer. 2022;32(7):931–8. Published 2022 Jul 4. 4. Onstad MA, Schmandt RE, Lu KH.  Addressing the role of obesity in endometrial cancer risk, prevention, and treatment. J Clin Oncol. 2016;34(35):4225–30. 5. Stewart HL, Birch DJS.  Fluorescence guided surgery methods. Appl Fluoresc. 2021;9:4. https://doi.org/10.1088/2050-­6120/ac1dbb.

484

L. Lipetskaia et al.

6. Pölcher M, Matz S, Braun M, Brambs C, Beer M, Hamann M. Sentinel lymph node mapping with indocyanine green compared to blue dye tracer in gynecologic malignancies-a single center experience of 218 patients. J Surg Oncol. 2021;123(4):1092–8. https://doi.org/10.1002/jso.26338. 7. Bodurtha Smith AJ, Fader AN, Tanner EJ. Sentinel lymph node assessment in endometrial cancer: a systematic review and meta-analysis. Am J Obstet Gynecol. 2017;216(5):459–476.e410. https://doi.org/10.1016/j. ajog.2016.11.1033. 8. Abu-Rustum NR, Yashar CM, Bradley K, Campos SM, Chino J, Chon HS, Chu C, Cohn D, Crispens MA, Damast S, et al. NCCN guidelines® insights: uterine neoplasms, version 3.2021. J Natl Compr Cancer Netw. 2021;19(8):888–95. https://doi.org/10.6004/jnccn.2021.0038. From NLM. 9. Peone AM, Casadio P, Formelli G, Levorato M, Ghi T, Costa S, Meriggiola MC, Pelusi G.  Cervical and hysteroscopic injection for identification of sentinel lymph node in endometrial cancer. Gynecol Oncol. 2008;111(1):62–7. https://doi.org/10.1016/j.ygyno.2008.05.032. 10. Rocha A, Domínguez AM, Lécuru F, Bourdel N. Indocyanine green and infrared fluorescence in detection of sentinel lymph nodes in endometrial and cervical cancer staging—a systematic review. Eur J Obstet Gynecol Reprod Biol. 2016;206:213–9. https://doi.org/10.1016/j. ejogrb.2016.09.027. 11. Ruscito I, Gaspai ML, Braicu EI, Bellati F, Raio L, Sehouli J, Mueller MD, Panici PB, Papadia A. Sentinel node mapping in cervical and endometrial cancer: Indocyanine green versus other conventional dyes-a meta-­ analysis. Ann Surg Oncol. 2016;23(11):3749–56. https://doi.org/10.1245/ s10434-­016-­5236-­x. 12. Ulain Q, Han L, Wu Q, Zhao L, Wang Q, Tuo X, Wang Y, Wang Q, Ma S, Sun C, et  al. Indocyanine green can stand alone in detecting sentinel lymph nodes in cervical cancer. J Int Med Res. 2018;46(12):4885–97. https://doi.org/10.1177/0300060518803041. 13. Levinson KL, Mahdi H, Escobar PF. Feasibility and optimal dosage of indocyanine green fluorescence for sentinel lymph node detection using robotic single-site instrumentation: preclinical study. J Minim Invasive Gynecol. 2013;20(5):691–6. https://doi.org/10.1016/j.jmig.2013.03.013. 14. Vahrmeijer AL, Hutteman M, van der Vorst JR, van de Velde CJ, Frangioni JV.  Image-guided cancer surgery using near-infrared fluorescence. Nat Rev Clin Oncol. 2013;10(9):507–18. https://doi.org/10.1038/nrclinonc.2013.123. 15. Naldini A, Vizzielli G, Peone E, Gallotta V, Scambia G. Robotic video endoscopic inguinal lymphadenectomy (R-VEIL) for vulvar cancer with sentinel node mapping using indocyanine green and near-infrared fluorescence imaging technology. Gynecol Oncol. 2018;150(1):203–4. https://doi.org/10.1016/j.ygyno.2018.04.568. 16. Kleppe M, Wang T, Van Gorp T, Slangen BF, Kruse AJ, Kruitwagen RF. Lymph node metastasis in stages I and II ovarian cancer: a review.

16  Use of Fluorescence Guidance in Gynecology

485

Gynecol Oncol. 2011;123(3):610–4. https://doi.org/10.1016/j. ygyno.2011.09.013. 17. Lago V, Bello P, Montero B, Matute L, Padilla-Iserte P, Lopez S, Marina T, Agudelo M, Domingo S. Sentinel lymph node technique in early-stage ovarian cancer (SENTOV): a phase II clinical trial. Int J Gynecol Cancer. 2020;30(9):1390–6. https://doi.org/10.1136/ijgc-­2020-­001289. 18. Uccella S, Nero C, Vizza E, Vargiu V, Coado G, Bizzai N, Ghezzi F, Cosentino F, Turco LC, Fagotti A, et al. Sentinel-node biopsy in early-­ stage ovarian cancer: preliminary results of a prospective multicentre study (SELLY). Am J Obstet Gynecol. 2019;221(4):324.e321–10. https:// doi.org/10.1016/j.ajog.2019.05.005. 19. Nguyen-Xuan HT, Montero Macias R, Bonsang-Kitzis H, Deloménie M, Ngô C, Koual M, Bats AS, Hivelin M, Lécuru F, Balaya V. Use of fluorescence to guide surgical resection in vulvo-vaginal neoplasia: two case reports. J Gynecol Obstet Hum Reprod. 2021;50(6):101768. https://doi. org/10.1016/j.jogoh.2020.101768. 20. Degett TH, Andersen HS, Gögenur I.  Indocyanine green fluorescence angiography for intraoperative assessment of gastrointestinal anastomotic perfusion: a systematic review of clinical trials. Langenbeck's Arch Surg. 2016;401(6):767–75. https://doi.org/10.1007/s00423-­016-­1400-­9. 21. Bizzai N, Foschi N, Loveo M, Tortorella L, Santullo F, Rosati A, Gueli Alletti S, Costantini B, Gallotta V, Feandina G, et al. Indocyanine green to assess vascularity of ileal conduit anastomosis during pelvic exenteration for recuent/persistent gynecological cancer: a pilot study. Front Oncologia. 2021;11:727725. https://doi.org/10.3389/fonc.2021.727725. 22. Nisolle M, Donnez J.  Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68(4):585–96. https://doi.org/10.1016/s0015-­ 0282(97)00191-­x. 23. De Neef A, Cadière GB, Bourgeois P, Barbieux R, Dapri G, Fastrez M. Fluorescence of deep infiltrating endometriosis during laparoscopic surgery: a preliminary report on 6 cases. Surg Innov. 2018;25(5):450–4. https://doi.org/10.1177/1553350618785486. 24. Bar-Shavit Y, Jaillet L, Chauvet P, Canis M, Bourdel N. Use of indocyanine green in endometriosis surgery. Fertil Steril. 2018;109(6):1136–7. https://doi.org/10.1016/j.fertnstert.2018.02.113. 25. Raimondo D, Mastronardi M, Mabrouk M, Cafagna G, Salucci P, Arena A, Iodice R, Borghese G, Casadio P, Del Forno S, et al. Rectosigmoid endometriosis vascular patterns at intraoperative Indocyanine green angiography and their coelation with clinicopathological data. Surg Innov. 2020;27(5):474–80. https://doi.org/10.1177/1553350620930147. 26. Lipetskaia LV. Near infrared imaging in robotically assisted urogynecologic surgery. AJOG. 2017;216:S619. 27. van der Sluis WB, Bouman MB, Al-Tamimi M, Meijerink WJ, Tuynman JB. Real-time indocyanine green fluorescent angiography in laparoscopic sigmoid vaginoplasty to assess perfusion of the pedicled sigmoid seg-

486

L. Lipetskaia et al.

ment. Fertil Steril. 2019;112(5):967–9. https://doi.org/10.1016/j.fertnstert.2019.08.063. From NLM. 28. Fontoura Oliveira A, Feeira H. Neovagina creation in congenital vaginal agenesis: new mini-laparoscopic approach applying intraoperative indocyanine green fluorescence. Surg Innov. 2021;28(1):24–32. https://doi. org/10.1177/1553350620968990. 29. Fuchs Weizman N, Einarsson JI, Wang KC, Vitonis AF, Cohen SL. Vaginal cuff dehiscence: risk factors and associated morbidities. JSLS. 2015;19(2):1. https://doi.org/10.4293/jsls.2013.00351. From NLM. 30. Beran BD, Shockley M, Arnolds K, Escobar P, Zimberg S, Sprague ML.  Laser angiography with Indocyanine green to assess vaginal cuff perfusion during total laparoscopic hysterectomy: a pilot study. J Minim Invasive Gynecol. 2017;24(3):432–7. https://doi.org/10.1016/j. jmig.2016.12.021. From NLM. 31. Nicholson K, Urh A, Demertzis K, Holubyeva A, LaPier Z, Cisneros-­ Camacho A, Goldberg GL, Schwartz B. Intraoperative Indocyanine green dye use in ovarian torsion: a feasibility study. J Minim Invasive Gynecol. 2022;29(6):738–42. https://doi.org/10.1016/j.jmig.2022.01.008. From NLM. 32. Ostrzenski A, Radolinski B, Ostrzenska KM. A review of laparoscopic ureteral injury in pelvic surgery. Obstet Gynecol Surv. 2003;58(12):794– 9. https://doi.org/10.1097/01.Ogx.0000097781.79401.0b. From NLM. 33. McGeady JB, Breyer BN. Cuent epidemiology of genitourinary trauma. Urol Clin North Am. 2013;40(3):323–34. https://doi.org/10.1016/j. ucl.2013.04.001. From NLM. 34. Dallas KB, Rogo-Gupta L, Elliott CS. Urologic injury and fistula after hysterectomy for benign indications. Obstet Gynecol. 2019;134(2):241– 9. https://doi.org/10.1097/aog.0000000000003353. From NLM. 35. Saidi MH, Sadler RK, Vancaillie TG, Akright BD, Farhart SA, White AJ.  Diagnosis and management of serious urinary complications after major operative laparoscopy. Obstet Gynecol. 1996;87(2):272–6. https:// doi.org/10.1016/0029-­7844(95)00411-­4. From NLM. 36. Redan JA, McCarus SD. Protect the ureters. JSLS. 2009;13(2):139–41. From NLM. 37. Huh WK, Johnson JL, Elliott E, Boone JD, Leath CA 3rd, Kovar JL, Kim KH. Fluorescence imaging of the ureter in minimally invasive pelvic surgery. J Minim Invasive Gynecol. 2021;28(2):332–341.e314. https://doi. org/10.1016/j.jmig.2020.06.022. 38. Fujita H, Kikuchi I, Nakagawa R, Katano M, Nakano E, Kitayama R, Tanaka Y. Use of a novel fluorescent catheter to locate the ureters during Total laparoscopic hysterectomy. J Minim Invasive Gynecol. 2021;28(7):1420–4. https://doi.org/10.1016/j.jmig.2021.04.004. 39. Ris F, Liot E, Buchs NC, Kraus R, Ismael G, Belfontali V, Douissard J, Cunningham C, Lindsey I, Guy R, et al. Multicentre phase II trial of near-­ infrared imaging in elective colorectal surgery. Br J Surg. 2018;105(10):1359–67. https://doi.org/10.1002/bjs.10844.

Future Directions in Fluorescence-and Image-­Guided Surgery

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Gene Yang

Introduction Fluorescence- and image-guided surgery are rapidly growing fields of research with a wide range of potential applications to bridge the gap between preoperative imaging and the operative environment. Fluorescence guidance systems have been utilized in many clinical applications across several disciplines to improve surgical outcomes, including tumor localization, anatomy identification, perfusion assessment, and lymphatic mapping [1]. Since the development of near-infrared fluorescent agents indocyanine green (ICG) and methylene blue, several additional fluorophores with varying fluorescence properties have been developed and validated for use in fluorescence guided surgery [2]. More recently, molecular and activatable fluorophores have emerged as alternatives to traditional fluorophores to expand the translation of this technology to additional surgical indications [3, 4]. Novel applications of several imaging technologies have provided additional methods for surgeons to make intraoperative image-based decision-making. A promising example is laser G. Yang (*) Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 N. Szoka et al. (eds.), The SAGES Manual of Fluorescence-Guided Surgery, https://doi.org/10.1007/978-3-031-40685-0_17

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speckle contrast imaging. Laser speckle contrast imaging (LSCI) is a noninvasive, real-time imaging technique that allows for ­perfusion assessment. This technology has been applied in the fields of cardiology, neurology, and dermatology. Validation studies have demonstrated LSCI as a potential valuable tool for perfusion assessment in laparoscopic surgery [5]. Augmented reality (AR) is another technology that is demonstrating increasing utility in image-guided surgery. AR can aid surgeons in the rapid identification of subsurface targets and structures, reduce surgeon’s cognitive load from mentally matching preoperative imaging to the operative environment, and guide resections with overlay of a virtual model onto the patient [6]. The purpose of this review is to provide an overview of the technology and recent developments in targeted fluorophores, LSCI, and AR.

Fluorescence-Guided Surgery Fluorescence-guided surgery (FGS) has developed into a validated method to augment surgeon’s ability to identify anatomic landmarks, localize tumors, and assess perfusion. Since the initial use of fluorescein in 1948 to localize intracranial neoplasms during neurosurgery, several additional fluorescent agents have been used for a variety of surgical applications. ICG initially used for quantitative measurement of hepatic and cardiac function has demonstrated clinical applications for perfusion assessment, cholangiography, lymphography, and tumor imaging. Methylene blue has been evaluated for ureter, thyroid, and neuroendocrine tumor assessment [7]. Five-Aminolevulinic acid and its derivative are clinically approved for imaging of malignant gliomas and bladder cancer with randomized controlled phase 3 trials demonstrating improved resection margin and increased progression-free survival for patients in these applications [8]. Recent focus has shifted from structural and functional fluorescence to molecular fluorescence, with subsequent developments resulting in fluorophores with increased specificity. In this method, tumor-specific ligands are conjugated to fluorescent dye, taking

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advantage of proven molecular probes and well-developed molecular pathology to aid in lesion detection and margin assessment during surgery and enable molecular targeted therapy with drug and photo-absorber conjugates [9]. Several therapeutic monoclonal antibodies have been repurposed for FGS by fluorescence conjugation. Bevacizumab conjugated with the fluorophore IRDye800CW has been applied in clinical feasibility studies to target tumors that overexpress vascular endothelial growth factor. The use of bevacizumab-­ IRDye800CW during cytoreductive surgery for peritoneal carcinomatosis of colorectal origin demonstrated additional detection of malignant lesions [10]. Application in breast surgery has demonstrated the ability of bevacizumab-IRDye800CW to assess tumor-positive margin during back-table assessment after breast conserving surgery [11]. Similar applications in head and neck surgery have demonstrated the ability of cetuximab-­ IRDye800CW to assess positive tumor margins on ex vivo back-­ table imaging, and panitumumab-IRDye800CW demonstrated feasibility in performing both in situ tumor imaging and ex vivo tumor margin assessment [12, 13]. An alternative approach is the use of activatable fluorescent probes. Activatable fluorescent probes seek to limit background signal by activating fluorescence after engaging the target. Compared to traditional fluorescent probes, activatable probes typically yield higher fluorescent signal and higher tumor-tobackground fluorescence ratio. A promising example of an activatable fluorescent probe is LUM015. LUM015, a PEGylated cathepsin-activated fluorescent imaging probe, is currently being investigated for detection of breast, gastrointestinal, brain, and prostate cancers. Initial studies demonstrated feasibility in tumorspecific fluorescence of sarcoma and breast cancer during ex vivo imaging and intraoperative detection of residual breast cancer [14]. Subsequent phase 2 study demonstrated improvement in final margin status sensitivity over standard pathology assessment of lumpectomy specimen. This was associated with reduced need for second surgery in patients who underwent intraoperative excision of fluorescence guided shaves [15].

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Limitations to Clinical Translation Molecular fluorescence imaging can provide additional information that augments the ability of a surgeon to see and treat pathology, but this technology remains in the early stages of development. Clinical studies consist mostly of early-phase trials conducted to evaluate the safety and optimal dosing of fluorescent agents and feasibility of intraoperative lesion detection. Further large, multicenter, randomized controlled trials are required to evaluate the diagnostic accuracy of fluorescence molecular imaging and impact on surgical outcomes. As the field of intraoperative molecular imaging matures, concurrent development of universal protocol for calibration and benchmarking of imaging devices to standardize the development and comparison of novel fluorescent agents will be essential [16, 17].

Laser Speckle Contrast Imaging LSCI has developed into a promising technology for image-­ guided surgery with current emphasis on intraoperative perfusion assessment. LSCI is based on the concept that tissue illuminated with coherent laser light backscatters in a random interference pattern, known as speckle pattern, onto a detector. When the speckle pattern is captured over an exposure time, movement of particles inside the tissue causes speckle pattern fluctuations resulting in changes in the speckle image. Fluctuations in tissue images due to movement of red blood cells allow for the assessment of tissue perfusion. The first in vivo application of LSCI on visceral organ perfusion in open surgery was reported by Eriksson et  al., demonstrating the feasibility of LSCI to measure hepatic microcirculation [18]. Subsequent studies with applications in porcine gastrointestinal tract and microvascular perfusion measurements of gastric conduit during esophagectomy further demonstrate the feasibility of using LSCI during gastrointestinal surgery [19, 20].

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More recent studies apply LSCI to the laparoscopic setting. Heeman et  al. demonstrated feasibility of a laparoscopic laser speckle contrast imaging setup to measure tissue perfusion during colon resection [21]. Comparison study of LSCI to ICG fluorescence imaging in intraoperative perfusion assessment during laparoscopic vascular occlusion of porcine intestine, stomach, and kidney demonstrated precise and accurate identification of demarcation between perfused and non-perfused tissue with both LSCI and ICG imaging. LSCI demonstrated an advantage over ICG with time-dependent perfusion assessment. Discordance in demarcation identification was noted in the ICG imaging group when images were assessed after 5  min from ICG administration [22]. Other novel developments in FGS include Activ Surgical, a company pioneering digital surgery imaging who has developed ActivSight, a modular imaging device which integrates with standard laparoscopic visualization systems to provide multimodal advanced visual intelligence. ActivSight enables visualization of ICG via its ActivICG module, as well as LCSI visualization via is ActivPerfusion module [23, 24].

Limitations to Clinic Translation Several limitations remain obstacles to the clinical use of LSCI. Initially introduced, LSCI was a qualitative method of perfusion assessment. Technical advancements such as introduction of multi-exposure speckle imaging now allow for quantitative assessments [25, 26]. LSCI is sensitive to motion as unwanted motion can be incorporated into the measured signal. In particular applications, such as intra-abdominal organ perfusion assessment, creating the required highly controlled environment is not always easily amenable. Recent studies have been published on motion artifact correction, but the need for a universal, real-time motion correction algorithm remains [5].

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Augmented Reality AR is a technology that superimposes computer-generated objects onto real images and video in real time, often described on a virtuality continuum between real environment (direct view of real environment) and virtual reality (immersion in a fully digital environment). Recent definitions of AR platforms require the combination of real and virtual environments to be interactive in real time and registered in 3D [27]. The application of AR to medical imaging data offers several advantages. Compared to the traditional method of viewing imaging data on a separate monitor, AR visualization eliminates the need for physicians to mentally transform imaging data onto a patient. This has broad applications within medicine but further profound implications for image-­ guided interventions. By using AR-guided surgery, the proceduralist’s attention is not divided between navigation method and the patient resulting in improved hand-eye coordination, accuracy, and time efficiency [28]. In addition, AR platforms enable stereoscopic/3D visualization of volumetric data to improve physician perception of imaging data to support the clinical decision-­ making process. Following is a review of current implementation of AR technology in surgery, as well as a brief description of the key technologies involved in developing AR platforms: medical imaging segmentation and modeling, tracking, registration, and visualization. AR systems are currently best implemented during surgery when there is little to no movement of the real environment and when tissue deformation is minimal, as these use cases require less tracking and processing power as compared to applications on mobile organs where tracking and display are significantly more complicated. Thus, clinical application of AR systems has been successfully implemented in the fields of neurosurgery, orthopedics, and otolaryngology, including for bone dissection, clipping of cerebral aneurysms, microvascular decompression, and placement of pedicle screws [29, 30]. AR systems have demonstrated accurate registration (0.2–3  mm), but increased

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operative time and potential associated financial costs have been reported with the use of AR systems for intraoperative guidance [31]. AR has been difficult to apply to abdominal surgery due to the amount of organ movement. Successful use cases have been reported for liver and pancreatic surgery, where AR has been used to compare the reconstructed virtual model with intraoperative ultrasound to identify lesions for resection [32]. Successful superimposed 3D representation of the patient’s hepatobiliary structures over the surgeon’s field of view has been studied during open liver surgery [33]. Intraoperative AR has been used to accurately detect sentinel lymph node using preoperative SPECT/CT scan [34]. Recently, RSIP Vision, a company specializing in image analysis and artificial intelligence for medical imaging, has developed RSIP Neph, an intraoperative AR tool that assists surgeons during partial nephrectomy to accurately locate and resect intracapsular renal lesions [35].

Image Segmentation The datasets presented from medical imaging are large, making them challenging to manipulate in real time. Image segmentation is the processing of medical imaging to isolate regions of interest and generate a model to interactively visualize the area. Identifying the relevant anatomy has traditionally been achieved by marking structures either manually or semi-autonomously within each individual image. Although several open-source packages are available to facilitate this process, image segmentation remains a limiting factor to clinical application of AR surgical guidance. Significant research efforts are underway to develop generalizable autonomous image segmentation; however, a proven and clinically accepted method is yet to be established because of similar contrast intensity between neighboring tissue, unclear lesion/target boundary, and variation in lesion/target shape [36].

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Registration The exact alignment of the virtual image to the real environment is crucial to the clinical application of AR platforms. Image registration is the process to determine the spatial correspondence of two or more image sets. In image-guided surgery, the two image sets are defined as a static and a moving set, and an algorithm is applied to determine the optimal translation that would minimize the difference seen between the virtual and real environment. The accurate alignment of both images can be achieved with a coordinate of trackers, used to determine the exact position and orientation of the camera and the patient’s body. Marker-based registration relies on rigid calibration of markers to real objects to allow for precise estimation of the real object as detected by either an external or internal sensor. Marker-free registration exploits the natural features observed by the tracking device within the real environment. An example of this is the simultaneous localization and mapping (SLAM) technique. More recent registration techniques integrate 3D surface information constructed directly by observing the real environment with stereoscopic cameras and time-of-flight depth sensors. The acquired surface can then be registered with a 3D model of the target [37]. Registration is complicated when the organ of interest does not behave as expected. This issue is particularly highlighted in general surgery where target anatomy is not rigid and deforms in a dynamic manner (ex. deformations with heartbeat and respiration). In addition, preoperative imaging is difficult to register to the real environment when attempting image-guided surgery during minimally invasive procedures as organs shift with laparoscopic insufflation and physical manipulation [38].

Limitations to Clinical Translation Although AR application in surgery has shown great promise through individual specialty applications and preclinical research,

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several issues limit the clinical translation of AR systems. ­Medical imaging continues to advance to provide more detail for preoperative planning, but the amount of data to be processed to segment image datasets are large, and current segmentation methods are time intensive. Further research is needed to identify generalizable segmentation methods [39]. Additional research is required to understand the challenges surgeons may encounter in utilizing augmented information in the operating room. Head-mounted displays may unintentionally obscure vision of the surgical field by decreasing the field of view or create visual clutter from the virtual model overlay. In addition, overlay displays may distract surgeons from the procedure. Surgeons may also encounter visual clutter or information overload where overlay outputs contain more information than the surgeon can meaningfully comprehend [40, 41]. Poor ergonomics with head-mounted displays may lead to fatigue, and virtual overlays may cause simulator sickness exhibited by nausea, headache, and vertigo [42, 43].

Conclusion Fluorescence- and image-guided surgery are evolving fields of study that have the potential to transform surgical care and improve patient outcomes. Development of novel targeted molecular fluorophores offer the possibility of accurate and precise in vivo tumor localization and margin assessment to guide complete resection. LSCI provides a noninvasive, real-time method to intraoperatively assess perfusion without the need for fluorophore administration. Advancements in image processing and registration are bringing surgeons closer to realizing reliable and accurate use of AR in the operating room. Significant barriers exist to the clinical translation of these technologies to the operative environment; however, these technologies remain areas of robust research, and the next decade will likely bring solutions which address said limitations and allow a larger audience to access these disruptive innovations.

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References 1. Alander JT, et al. A review of indocyanine green fluorescent imaging in surgery. J Biomed Imaging. 2012;2012:7–7. 2. Stewart HL, Birch DJS.  Fluorescence guided surgery. Methods Appl Fluoresc. 2021;9(4):042002. 3. Haque A, et al. Next generation NIR fluorophores for tumor imaging and fluorescence-guided surgery: a review. Bioorg Med Chem. 2017;25:7. 4. Zhang Y, et al. Activatable molecular probes for fluorescence-guided surgery, endoscopy and tissue biopsy. Chem Soc Rev. 2022;51(2):566–93. 5. Heeman W, et al. Clinical applications of laser speckle contrast imaging: a review. J Biomed Opt. 2019;24(8):080901–1. 6. Barcali E, et al. Augmented reality in surgery: a scoping review. Appl Sci. 2022;12(14):6890. 7. Hillary SL, Guillermet S, Brown NJ, Balasubramanian SP. Use of methylene blue and near-infrared fluorescence in thyroid and parathyroid surgery. Langenbecks Arch Surg. 2018;403(1):111–8. https://doi. org/10.1007/s00423-­017-­1641-­2. Epub 2017 Dec 11. PMID: 29230539; PMCID: PMC5805804. 8. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, ALA-Glioma Study Group. Fluorescence-guided surgery with 5-­aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401. https://doi.org/10.1016/S1470-­2045(06)70665-­9. PMID: 16648043. 9. Nagaya T, et al. Fluorescence-guided surgery. Front Oncol. 2017;7:314. 10. Harlaar NJ, et  al. Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study. Lancet Gastroenterol Hepatol. 2016;1(4):283–90. 11. Lamberts LE, et al. Tumor-specific uptake of fluorescent bevacizumab– IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study targeted near-infrared fluorescence imaging in breast cancer. Clin Cancer Res. 2017;23(11):2730–41. 12. Rosenthal EL, et  al. Sensitivity and specificity of cetuximab-­ IRDye800CW to identify regional metastatic disease in head and neck cancer. Clin Cancer Res. 2017;23(16):4744–52. 13. van Keulen S, et al. Rapid, non-invasive fluorescence margin assessment: Optical specimen mapping in oral squamous cell carcinoma. Oral Oncol. 2019;88:58–65. 14. Smith BL, et  al. Real-time, intraoperative detection of residual breast cancer in lumpectomy cavity walls using a novel cathepsin-activated fluorescent imaging system. Breast Cancer Res Treat. 2018;171:413–20.

17  Future Directions in Fluorescence-and Image-Guided Surgery

497

15. Hwang ES, et al. Clinical impact of intraoperative margin assessment in breast-conserving surgery with a novel pegulicianine fluorescence– guided system: a nonrandomized controlled trial. JAMA Surg. 2022;157(7):573–80. 16. Souza D, Alisha V, et al. Review of fluorescence guided surgery systems: identification of key performance capabilities beyond indocyanine green imaging. J Biomed Opt. 2016;21(8):080901–1. 17. Pogue BW, et  al. Perspective review of what is needed for molecular-­ specific fluorescence-guided surgery. J Biomed Opt. 2018;23(10):100601– 1. 18. Eriksson S, et al. Laser speckle contrast imaging for intraoperative assessment of liver microcirculation: a clinical pilot study. Med Devices. 2014;7:257–61. 19. Ambrus R, et al. Evaluation of gastric microcirculation by laser speckle contrast imaging during esophagectomy. J Am Coll Surg. 2017;225(3):395–402. 20. Milstein DMJ, et al. Laser speckle contrast imaging identifies ischemic areas on gastric tube reconstructions following esophagectomy. Medicine. 2016;95:25. 21. Heeman W, et al. Application of laser speckle contrast imaging in laparoscopic surgery. Biomed Opt Express. 2019;10(4):2010–9. 22. Nwaiwu CA, et  al. Feasibility and comparison of laparoscopic laser speckle contrast imaging to near-infrared display of indocyanine green in intraoperative tissue blood flow/tissue perfusion in preclinical porcine models. Surg Endosc. 2022;37:1–10. 23. Sanders CM, Nwaiwu CA, Liu YZ, Panchal AN, Butsch JL, Hoffman AB, Posner AR, Falvo MA, Visco J, Ortolani JB, Barone SM, Burstein MD, DeJesus C, Bouvy ND, Boni L, Shah SK, Wilson EB, Dechert AF, Buharin VE, Schwaitzberg SD, Kim PCW. ActivSightTM dye-less visualization of tissue perfusion in MIS surgery: interim analysis of first clinical (n=66) and preclinical (n=20) Studies with ICG comparison. World Congress of Endoscopic Surgery/European Association of Endoscopic Surgery 2021. Presentation date: November 24, 2021. 24. Shah SK, Nwaiwu CA, Agarwal AK, Bajwa KS, Felinksi MM, Walker PA, Wilson TD, Dechert AF, Kim PCW, Wilson EB.  First-In-Human (FIH) Safety, feasibility, & usability trial (NCT# 04633512) of a laparoscopic imaging device using laser speckle contrast imaging (LSCI). In: Visualizing real-time tissue perfusion and blood flow without fluorophore in colorectal and bariatric patients, vol. 233. Boston: American College of Surgeons Clinical Congress; 2021. p. S45. Presentation date: October 24, 2021.

498

G. Yang

25. Parthasarathy AB, et al. Robust flow measurement with multi-exposure speckle imaging. Opt Express. 2008;16(3):1975–89. 26. Richards LM, et  al. Intraoperative multi-exposure speckle imaging of cerebral blood flow. J Cereb Blood Flow Metab. 2017;37(9):3097–109. https://doi.org/10.1177/0271678X16686987. 27. Gupta A, Ruijters D, Flexman ML. Augmented reality for interventional procedures. In: Digital surgery. Cham: Springer; 2021. p. 233–46. 28. Shuhaiber JH. Augmented reality in surgery. Arch Surg. 2004;139(2):170– 4. 29. Gmeiner M, Dirnberger J, Fenz W.  Virtual cerebral aneurysm clipping with real-time haptic force feedback in neurosurgical education. World Neurosurg. 2018;112:e313–23. 30. Xin B, Chen G, Wang Y. The efficacy of immersive virtual reality surgical simulator training for pedicle screw placement: a randomized double-­ blind controlled trial. World Neurosurg. 2018;124:e324–30. 31. Kang X, et al. Stereoscopic augmented reality for laparoscopic surgery. Surg Endosc. 2014;28(7):2227–35. 32. Tanagho YS, Andriole GL, Paradis AG, Madison KM, Sandhu GS, Varela JE, Benway BM. 2D versus 3D visualization: impact on laparoscopic proficiency using the fundamentals of laparoscopic surgery skill set. J Laparoendosc Adv Surg Tech A. 2012;22(9):865–70. https://doi. org/10.1089/lap.2012.0220. Epub 2012 Oct 16. 33. Gavaghan KA, et  al. A portable image overlay projection device for computer-­ aided open liver surgery. IEEE Trans Biomed Eng. 2011;58(6):1855–64. 34. Wendler T, et al. First demonstration of 3-D lymphatic mapping in breast cancer using freehand SPECT.  Eur J Nucl Med Mol Imaging. 2010;37(8):1452–61. 35. https://www.rsipvision.com/rsip-­neph/. 36. Herline AJ, Stefansic JD, Debelak JP, et al. Image-guided surgery: preliminary feasibility studies of frameless stereotactic liver surgery. Arch Surg. 1999;134:644. 37. Mountney P, Yang G-Z. Motion compensated SLAM for image guided surgery. Medical image computing and computer-assisted intervention– MICCAI.  In: 13th international conference, Beijing, China, September 20–24, 2010, proceedings, part II 13. Berlin: Springer; 2010. p. 2010. 38. Bernhardt S, Nicolau SA, Soler L, Doignon C. The status of augmented reality in laparoscopic surgery as of 2016. Med Image Anal. 2017;37:66– 90. 39. Vávra P, et  al. Recent development of augmented reality in surgery: a review. J Healthc Eng. 2017;2017:1. 40. Guanà R, Ferrero L, Garofalo S, Cerrina A, Cussa D, Arezzo A, Schleef J. Skills comparison in pediatric residents using a 2-dimensional versus a 3-dimensional high-definition camera in a pediatric laparoscopic simulator. J Surg Educ. 2017;74(4):644–9. https://doi.org/10.1016/j. jsurg.2016.12.002. Epub 2016 Dec 27.

17  Future Directions in Fluorescence-and Image-Guided Surgery

499

41. Pratt P, Stoyanov D, Visentini-Scarzanella M, Yang GZ. Dynamic guidance for robotic surgery using image-constrained biomechanical models. In: In international conference on medical image computing and computer-­assisted intervention. Springer; 2010. p. 77–85. 42. Condino S, Carbone M, Piazza R, Ferrari M, Ferrari V. Perceptual limits of optical see-through visors for augmented reality guidance of manual tasks. IEEE Trans Biomed Eng. 2020;67(2):411–9. 43. Edwards PJ, et  al. The challenge of augmented reality in surgery. In: Digital surgery. Cham: Springer; 2021. p. 121–35.

Index

A Absolute perfusion units (APUs), 37 Activatable fluorescent probes, 489 ActivPerfusion module, 491 ActivSight™, 71, 72 Acute care surgery (ACS) AMI, 315–319 bowel perfusion, 320, 321 coding, 315, 321 dosing and administration, 314 history and physiology, 308, 309 laparoscopic cholecystectomy, 310–314 SBO, 319, 320 Acute mesenteric ischemia (AMI), 315–319 Adrenal surgery challenges, 179 fluorescent imaging guidance, 180–183 limitations, 182, 183 results, 183, 184 symptoms, 179 technical errors, 180 1688 Advanced imaging modalities (AIM) 4K platform

advantages and disadvantages, 60 components, 55, 58 dosing, timing, and route of administration, 58–60 overview, 55, 56 Alagille syndrome, 373 Anastomotic leaks (AL) clinical and economic outcomes, 88 gain, 93 index hospitalization, 88 rates, 88, 89 risk factors, 88 RYGB, 205–207 technical aspects, 90–95 timing, 92, 93 ureters, 95, 96 Arteriovenous malformations (AVM), 393 Augmented reality (AR), 488, 493 abdominal surgery, 493 image segmentation, 493 implementation, 492 limitations, 494, 495 platforms, 492 registration, 494

© Society of American Gastrointestinal and Endoscopic Surgeons 2023 N. Szoka et al. (eds.), The SAGES Manual of Fluorescence-Guided Surgery, https://doi.org/10.1007/978-3-031-40685-0

501

502 B Background-subtracted peak fluorescence intensity (BSFI), 421 Bariatric surgery BPD/DS advantages and disadvantages, 212, 213 cholecystectomy, 214 ICG, 211, 212, 214, 215 incidence and management, 210, 211 intraluminal ICG, 213, 214 overview, 208, 209 technique, 209, 210 revisional procedure endolumik fluorescence guided gastric calibration tube, 218–222 GJ anastomosis, 218 indications, 216 LAGB, 216, 217 SG to RYGB, 217, 218 RYGB anastomotic leaks, 205–207 ICG, 208 intraluminal ICG leak, 207, 208 procedures and results, 203, 204 technique, 205 sleeve gastrectomy benefits, 194 cause of leak, 196, 197 disadvantage, 195 ICG angiography, 198, 201 intraluminal ICG, 202, 203 intraoperative application, 197–200 leak rates, 195, 196 technique, 195 Bevacizumab-IRDye800CW, 489 Biliopancreatic diversion with duodenal switch (BPD/ DS) advantages and disadvantages, 212, 213

Index cholecystectomy, 214 ICG, 211, 212, 214, 215 incidence and management, 210, 211 intraluminal ICG, 213, 214 overview, 208, 209 technique, 209, 210 Breast cancer-related lymphedema (BCRL), 242 Breast reconstruction autologous reconstruction clinical evaluation vs. indocyanine green laser angiography, 240 complications, 240 cost effectiveness, 240, 241 flap perfusion, 239 liposuction, 240 lymphedema surgery, 241–245 operative times and length of hospital stay, 238 patient factors, 240 breast mastectomy flaps, 247 contraindications and adverse reactions, 250, 253 history, 232, 233 implant-based reconstruction immediate reconstruction, 235–237 tissue expander, 237, 238 indications, 235 lymphaticovenous anastomosis, 248, 249 mechanism of action, 233 medications, 247 SPY Agent Green, 246 Burn surgery clinical assessment, 279 laser doppler imaging, 281 pathological study, 280 thermography, 280 ultrasound, 281 ICGA (see Indocyanine green angiography (ICGA)) incidence, 276 nonfatal burns, 276

Index pathophysiology, 276–279 C Camera control unit (CCU), 313 Carcinoembryonic antigen (CEA), 20, 113 Cardiac surgery, 372, 373 Cervical cancer, 465–467 Cetuximab-IRDye800CW, 489 Chromophore, 9, 10 Chylothorax, 356, 357 Colorectal surgery literature review, 96–103 liver metastasis detection, 107 dosage and timing of administration, 106, 107 fluorescence pattern, 105, 106 overview, 105 resection margin, 107, 108 lymphatic mapping, 109–113 peritoneal carcinomatosis, 103, 104 pulmonary metastasis, 108 Common bile duct (CBD), 313, 343 Common hepatic duct (CHD), 343 CPT code 15860, 271 Critical view of safety (CVS), 343 D Deep Inferior Epigastric artery Perforator flap (DIEP), 245 E EleVision IR Platform, 63, 64 advantages and disadvantages, 66 components, 63, 65 Endocrine surgery adrenal surgery challenges, 179 fluorescent imaging guidance, 180–183

503 limitations, 182, 183 results, 183, 184 symptoms, 179 technical errors, 180 autofluorescence, 158, 159 clinical results, 422–424 disadvantages, 424, 425 graft patency coronary angiography, 404 IFI, 408–414 TTFM (see Transient time flowmetry) validation studies, 414–418 indications, 403, 404 interpretation, 418–422 NIR imaging system, 158, 159 parathyroid surgery autofluorescence, 172, 173 fluorescent dyes, 173–175 indication, 171 limitations, 174, 176 preoperative imaging, 172 results, 176–179 pediatric heart surgery coronary anatomy, 428, 429 coronary artery implantation, 426 IGFA, 426 intraoperative fluorescent imaging, 430 limitations, 427 modality, 426 palliative shunt, 427 pulmonary artery reconstruction, 427 vessel/anastomotic site patency, 428 randomized controlled trial, 185 system development, 160, 161 thyroid surgery autofluorescence, 162–164 factors, 161 fluorescent dyes, 164–168 life-threatening symptoms, 162 limitations, 166, 167, 169 results, 169–171

504 Endolumik fluorescence guided gastric calibration tube, 75–79, 218–222 Endometrial cancer (EC), 464–466 Endometriosis, 470–473 Extracranial-intracranial (EC-IC) bypass, 394–397

Index revisions, 474–476 tumor lymphatic imaging cervical cancer, 465–467 endometrial cancer, 464–466 ovarian cancer, 467, 468 vulva cancer, 467 tumor margin detection, 468, 469 ureter visualization, 478–480

F Firefly, 69 advantages and disadvantages, 71 components, 68 dosing, timing, and route of administration, 70 instructions for use, 69, 70 Flash fluorescence technique, 396 Fluobeam LX system, 44 advantages and disadvantages, 46 components, 43, 45 Fluobeam® 800 clinical system, 290 Fluorophores, 8, 9

H Hepatectomy biliary ductal anatomy, 136–140 PHLF, 149, 150 primary and metastatic liver tumors, 140–144 segmentation, 144–149 vascular structures identification, 144–149 Hepatobiliary surgery, 342 Hepatoblastoma (HB), 345, 348 Hepatocellular carcinomas (HCC), 106

G Gastrojejunostomy (GJ), 205, 218 Glutathione S-transferase, 16 Green Egg, 72–74 Gynecology bowel and GU anastomosis, 469–471 endometriosis, 470–473 fluorescent angiography ovarian torsion, 476–478 vaginal cuff angiography, 476, 477 fluorescent medical devices, 479, 481, 482 incidence, 463 pelvic reconstructive procedures Burch colposuspension, 473 neovagina construction, 473, 474

I ICG fluorescent cholangiography (ICG-FC), 342, 343 Image 1S Rubina, 60–63 Immunofluorescence chromophore, 9, 10 clinical requirement, 2 devices, 26 excitation source, 23, 24 extrinsic probes advantages, 12 5-ALA, 18–20 clinical development, 20, 21 fluorescein sodium, 13, 14 ICG, 15–18 methylene blue, 14, 15 regulatory requirements, 13 features, 25

Index fluorescence system detector, 24, 25 fluorescence system filters, 24 fluorophores, 8, 9 intrinsic probes, 11, 12 NIR wavelength, 21–23 optical imaging, 3 principles, 7, 8 properties, 22 radiological imaging, 3 reports of, 4, 5 in surgery, 4–7 Indocyanine green (ICG), 15–18, 33 BPD/DS, 214, 215 RYGB, 208 sleeve gastrectomy, 198, 201 Indocyanine green angiography (ICGA), burn surgery advantages and disadvantages, 283 appropriate time, marking, 295, 296 burn excision, 285, 286 commercial marking pen, 296, 297 features, 282 generalizability, 297 immobilization, 283 interpretation, 294, 295 intervention, 287–291 limitations, 282, 298 objective interpretation criteria, 291–294 pain and easy-to-erase problems, 297 pathologic tissue evaluation, interpretation, and clinical outcomes, 286, 287 quantitative interpretation, 284 superficial and deep burn wounds, 281 wound closure, 296 Indocyanine green fluorescence imaging (ICG-FI)

505 anastomotic leaks clinical and economic outcomes, 88 gain, 93 index hospitalization, 88 rates, 88, 89 risk factors, 88 technical aspects, 90–95 timing, 92, 93 ureters, 95, 96 colorectal surgery (see Colorectal surgery) Infrared illuminating system (IRIS) ureteral kit, 74, 75 Intestinal resection and anastomosis, 348–350 Intraluminal ICG, 202, 203 BPD/DS, 213, 214 RYGB, 207, 208 Intraoperative fluorescence imaging (IFI) system advantage and disadvantage, 411–414 principle, 408, 409 techniques, 409–411 Intraoperative vessel identification, 395 J Jejunojejunostomy, 205 K Kasai portoenterostomy (KPE), 345 L Laparoscopic adjustable gastric band (LAGB), 216, 217 Laparoscopic cholecystectomy (LC) advantages, 128, 129 limitations, 130 literature review, 125–128

506 Laser speckle contrast imaging (LSCI), 490, 491 Light emitting diodes (LEDs), 23 Liver metastasis detection, 107 dosage and timing of administration, 106, 107 fluorescence pattern, 105, 106 overview, 105 resection margin, 107, 108 Liver transplant surgery, 357–359 LUM015, 489 Lung metastasis, 355, 356 Lymphaticovenous anastomosis (LVA), 245 Lymphatic-sparing varicocelectomy, 445, 446, 456–459 M Marker-free registration, 494 Methylene blue (MB), 14, 15 Middle meningeal artery (MMA), 374 Moyamoya disease, 374 N Nearinfrared (NIR) wavelength, 21–23 Neurosurgery, 373–376 aneurysm repair, 387–393 AVM, 393 extracranial-intracranial bypass, 394–397 history, 385 standard ICG dosing, 398 Neurovascular bundle (NVB), 455 Novadaq SPY system, 33 O Open surgical system, 34 Ovarian cancer (OC), 467, 468 Ovarian torsion, 476–478

Index P Parathyroid surgery autofluorescence, 172, 173 fluorescent dyes, 173–175 indication, 171 limitations, 174, 176 preoperative imaging, 172 results, 176–179 Partial nephrectomies, 352, 353 Pediatric surgery anatomy, 338 cardiac surgery, 372, 373 dosing and timing, 340 guidelines, 341, 342 heart surgery coronary anatomy, 428, 429 coronary artery implantation, 426 IGFA, 426 intraoperative fluorescent imaging, 430 limitations, 427 modality, 426 palliative shunt, 427 pulmonary artery reconstruction, 427 vessel/anastomotic site patency, 428 hepatobiliary surgery, 342 hepatoblastoma, 345, 348 intestinal resection and anastomosis, 348–350 KPE, 345 laparoscopic cholecystectomy, 342, 343 liver transplant surgery, 357–359 neurosurgery, 373–376 oncology lymph node identification and SLNB, 366, 368, 369 non-hepatic primary tumor resection, 361–363 primary hepatic tumor resection, 360, 361

Index pulmonary metastasectomy, 363, 365 plastic surgery, 369–371 scientific basis, 338, 339 side effects and complications, 340 thoracic surgery chylothorax, 356, 357 congenital pulmonary lesions, 355 lung metastasis, 355, 356 segmentectomy, 354 trauma surgery, 371, 372 urology cyst deroofing, 354 intraoperative ureteral identification, 350, 351 partial nephrectomies, 352, 353 varicocele, 353 Pediatric urology cyst deroofing, 354 intraoperative identification, 350, 351 partial nephrectomies, 352, 353 varicocele, 353 Pelvic lymph node dissection (PLND), 441 Peritoneal carcinomatosis (PC), 103, 104 Photodynamic eye (PDE)-neo II infrared fluorescence imager advantages and disadvantages, 43 components, 40, 41 dosing, timing, and route of administration, 42 PILLAR (perfusion assessment in left-sided/low anterior resection) trial, 46 Pinpoint endoscopic fluorescence imaging system advantages and disadvantages, 49

507 components, 47, 48 dosing, timing, and route of administration, 48, 49 Plastic and reconstructive surgery abdominoplasty and panniculectomy, 265–268 complications, 259 documentation and medical coding, 271 extremity reconstruction, 259–263 indocyanine green, 258, 268, 269 near-infrared, 258 skin flaps, 263, 264 SPY-Q system, 268 timing of dye administration intraoperative, 269, 270 postoperative, 270, 271 preoperative, 269 Plastic surgery, 369–371 Posthepatectomy liver failure (PHLF), 149, 150 Prostate cancer, 444, 445, 455–458 Pulmonary metastasectomy non-hepatic tumors, 365 primary hepatic tumors, 363 Q Quest spectrum, 66 advantages and disadvantages, 68 components, 67, 68 R Revascularization surgery, 374 Roux-en-Y gastric bypass (RYGB), 217, 218 anastomotic leaks, 205–207 ICG, 208 intraluminal ICG leak, 207, 208 procedures and results, 203, 204 technique, 205

508 S Sentinel lymph node (SLN) mapping, 109 Sentinel lymph node biopsy (SLNB), 366, 368, 369 Simultaneous localization and mapping (SLAM) technique, 494 Single anastomosis duodenoileostomy with sleeve gastrectomy (SADI-S), 209 Skin flaps, 263–265 Sleeve gastrectomy (SG), 217, 218 benefits, 194 cause of leak, 196, 197 disadvantage, 195 ICG angiography, 198, 201 intraluminal ICG, 202, 203 intraoperative application, 197–200 leak rates, 195, 196 technique, 195 Small bowel obstructions (SBO), 319, 320 SPY elite system, 35 components, 35 dosing, timing, and route of administration, 36, 37 SPY- portable handheld imaging (PHI) system, 37–40, 320–321 SPY-Q system, 259, 260 Stomach-intestinal pyloric sparing (SIPS), 209 SynergyID advantages and disadvantages, 53 components, 50–52

Index T Thoracic surgery chylothorax, 356, 357 congenital pulmonary lesions, 355 lung metastasis, 355, 356 segmentectomy, 354 Thyroid surgery autofluorescence, 162–164 factors, 161 fluorescent dyes, 164–168 life-threatening symptoms, 162 limitations, 166, 167, 169 results, 169–171 Transient time flowmetry (TTFM) experience and results, 406–408 limitations, 408 technique, 405, 406 Trauma surgery, 308, 321–326 coding, 327 fluorescence guidance and wound care, 328 skin flap perfusion, 327 U Ureteroenteric strictures (UES), 443 Urologic surgery anastomotic leak and strictures, 435 identification, 436–438, 448 indocyanine green, 436 kidney transplantation, 446, 447 lymphatic-sparing varicocelectomy, 445, 446, 456–459 partial nephrectomy, 440, 441, 449–452

Index prostate cancer, 444, 445, 455–458 reconstruction, 437–439, 448, 449 urinary diversion, 441–444, 451, 453, 455 urothelial cell carcinoma, 441–444, 451, 453, 455

509 V Vascularized lymph node transfer (VLNT), 245 Visera Elite II Infrared imaging system, 53 advantages and disadvantages, 55 components, 54, 55 Vulva cancer, 467